Technical Field
[0001] The present invention relates to a phenylimidazole derivative and therapeutic medicine
or preventive medicine for inflammatory diseases, diseases caused by lipid oxidation,
or retinochoroidal disorders, including at least one selected from the derivative
as an active ingredient.
Background Art
[0003] Inflammation is tissue reaction and systemic reaction against invasion to the body.
Examples of invasion that cause inflammation include external stimuli such as wounds,
infections, intrusion of antigenic substances (allergic reactions), and internal stimuli
generated in the body such as cell injury. In addition, inflammation advances and
worsens due to prostaglandin or leukotriene, both mediators of inflammation. An inflammation
reaction is an important physiological reaction, but an extreme inflammation reaction
causes significant damage to the body. For this reason, various kinds of anti-inflammatory
agents have been developed. Anti-inflammatory agents currently in use are generally
classified as either non-steroidal anti-inflammatory agents or steroidal anti-inflammatory
agents. A non-steroidal anti-inflammatory agent is operated by biosynthesis inhibition
of prostaglandin due to inhibition of activity of cyclooxygenase. Meanwhile, a steroidal
anti-inflammatory agent binds to a receptor in cytoplasm and incorporated into the
nucleus, activates specific genes, and induces biosynthesis of lipocortin. It is known
that lipocortin shows anti-inflammatory actions through inhibition of various chemical
mediators. The actions include cyclooxygenase pathway inhibition through phospholipase
A2 inhibition, or a lipoxygenase pathway inhibition through leukotriene B4 inhibition.
[0004] Meanwhile, when a retina receives light from the outside, the energy thereof is absorbed
by visual substances (rhodopsin) which are present in inner segments and outer segments
of visual cells and converted to an electrical signal. A conduction path of vision
in cells is visual cells, bipolar cells, and ganglion cells in order. After the electrical
signal passes through a path of vision, the electrical signal is transmitted to a
visual cortex in the occipital lobe of the cerebrum, and is then perceived as an image.
In outer segments of visual cells in which visual substances are present, since a
large amount of higher unsaturated fatty acids such as docosahexaenoic acid and arachidonic
acid are present, the visual cells tend to be easily degenerated. Further, since degeneration
of visual cells is almost irreversible, the degeneration is a factor of serious vision
impairment. The degeneration of vision cells occurs for genetic reasons, but it is
also known that visual cells degenerate due to various kinds of oxidation stresses
such as light (ultraviolet rays), iron, oxygen, and radiation. Particularly, light
received by the eyes throughout life is a typical example of an oxidation stress in
retinas and is considered to be a main factor of retinochoroidal disorders.
[0005] A retinochoroidal disorder, especially a typical retinochoroidal disease accompanied
with retinal light disorders, includes age-related macular degeneration (hereinafter,
referred to as "AMD"). AMD is a disease that causes degeneration of a macular region
of a retina with age and is continuously increasing with the advancement of an aging
society. Particularly, in the west, AMD is highly ranked as a cause of late-eye blindness.
AMD is divided into exudative AMD (hereinafter, referred to as "Wet AMD") which causes
subretinal hemorrhage, edema, and serous retinal detachment accompanied by newborn
blood vessels generated from choroid and atrophy AMD (hereinafter, referred to as
"Dry AMD") that shows map-like atrophy lesions of retinal pigment epithelial cells
or choriocapillaris which are not accompanied by newborn blood vessels generated from
choroid. In addition, Wet AMD progresses rapidly and the prognosis worsens. Further,
Wet AMD causes serious visual impairment. Meanwhile, Dry AMD progresses slowly, but
causes advanced visual impairment when the lesions spread into macular regions. Moreover,
it is considered that both are progressive types and highly likely to be binocular.
[0006] For treatments of Wet AMD, photodynamic therapy, laser treatments (laser photocoagulation),
and surgical treatments (neovascular removal therapy and central fovea moving therapy)
are used, but there are various problems in the prognosis and treatment satisfaction
is extremely low. Moreover, as medical treatments, therapeutic medicine related to
VEGF has also been developed, but the therapeutic effects are not satisfactory because
of the administration route and side effects. Further, in regard to Dry AMD, medical
treatments are almost not performed.
[0007] In addition, as medicine used for treatments of retinochoroidal disorders, PTL 1
or 2 discloses a dihydrobenzofuran derivative having an excellent antioxidant action
and excellent tissue migration properties.
Citation List
Patent Literature
Summary of Invention
Technical Problem
[0009] Non-steroidal anti-inflammatory agents are generally used because of high safety,
but the anti-inflammatory action is not necessarily strong. Meanwhile, steroidal anti-inflammatory
agents show a significant inhibitory action with respect to inflammation and are also
effective in autoimmune diseases, but the side effects thereof are problematic. For
this reason, development of an anti-inflammatory agent whose action is strong and
which has high safety has been required. An object of the present invention is to
provide an active ingredient of a pharmaceutical product which is useful for treatment
or prevention of diseases caused by an inflammatory reaction.
[0010] As cell membrane disorders, particularly, nerve cell membrane disorders, disorders
caused by cerebral ischemia, excitotoxicity, or Aβ-toxicity are exemplary examples.
Further, in regard to the cerebral ischemia and excitotoxicity, disorders accompanied
by stroke, cerebral infarction, or cerebral embolism are exemplary examples. Moreover,
12/15-lipoxygenase and lipid peroxidase are enzymes that promote oxidation of lipids,
and it is reported that amyloid beta which is a causative substance of Alzheimer's
disease is excessively generated due to acceleration of 12/15-lipoxygenase (
NIH Public Access, 2012; vol. 71; pp. 56 to 67). Moreover, it is considered that 12/15-lipoxygenase is involved in the progress
of arteriosclerosis by oxidizing esterified polyunsaturated fatty acids of low-density
lipoprotein (LDL) (
The Japanese Pharmacological Society 2004; 124; 415 to 425). An object of the present invention is to provide an active ingredient of a pharmaceutical
product which is useful for treatment or prevention of diseases caused by lipid oxidation.
[0011] In the derivative described in PTL 1 or 2, there is a variation in treatment effects
or preventive effects in experiments performed on animal models of retinal light disorders.
Another object of the present invention is to provide an active ingredient of a pharmaceutical
product which is useful for treatment or prevention of retinochoroidal disorders.
Solution to Problem
[0012] As a result of examination performed by the present inventors in order to solve the
above-described problems, they found a phenylimidazole derivative having a specific
structure. It is found that effects in a treatment or prevention of inflammatory diseases,
diseases caused by lipid oxidation, or retinochoroidal disorders are significant when
the derivative or a salt thereof is contained in medicines as an active ingredient.
The present invention has been completed based on this knowledge.
[0013] The present invention includes the following aspects.
[1] A phenylimidazole derivative represented by Formula (I) or (II), or a salt thereof.
[0014] (In Formula (I), A represents a carbon atom or a nitrogen atom; B
1 represents a carbonyl group, a group represented by N-COR
1a, a group represented by N-C(R
1a)=NOH, or a group represented by N-SO
2R
1b; R
1a represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkyl group
which is substituted with G
1 and has 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkenyl
group which is substituted with G1 and has 2 to 6 carbon atoms, an alkynyl group having
2 to 6 carbon atoms, an alkynyl group which is substituted with G
1 and has 2 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, a cycloalkyl
group which is substituted with G
1 and has 3 to 8 carbon atoms, a hydroxyl group, an alkoxy group having 1 to 6 carbon
atoms, an alkoxy group which is substituted with G
1 and has 1 to 6 carbon atoms, an alkenyloxy group having 2 to 6 carbon atoms, an alkenyloxy
group which is substituted with G
1 and has 2 to 6 carbon atoms, an alkynyloxy group having 2 to 6 carbon atoms, an alkynyloxy
group which is substituted with G
1 and has 2 to 6 carbon atoms, an amino group, an amino group substituted with one
G
2, or an amino group substituted with two G
2s which are the same as or different from each other (in a case where the amino group
is substituted with two G
2s, two G
2s may be bonded to each other to form a ring); R
1b represents an alkyl group having 1 to 6 carbon atoms, an alkyl group which is substituted
with G
1 and has 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkenyl
group which is substituted with G
2 and has 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, an alkynyl
group which is substituted with G
1 and has 2 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, a cycloalkyl
group which is substituted with G
1 and has 3 to 8 carbon atoms, a hydroxyl group, an alkoxy group having 1 to 6 carbon
atoms, an alkoxy group which is substituted with G
1 and has 1 to 6 carbon atoms, an alkenyloxy group having 2 to 6 carbon atoms, an alkenyloxy
group which is substituted with G
1 and has 2 to 6 carbon atoms, an alkynyloxy group having 2 to 6 carbon atoms, an alkynyloxy
group which is substituted with G
1 and has 2 to 6 carbon atoms, an amino group, an amino group substituted with one
G
2, or an amino group substituted with two G
2s which are the same as or different from each other (in a case where the amino group
is substituted with two G
2s, two G
2s may be bonded to each other to form a ring); G
1 represents a halogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon
atoms, an amino group, or an amino group substituted with an alkyl group having 1
to 6 carbon atoms; G
2 represents an alkyl group having 1 to 6 carbon atoms, an alkyl group which is substituted
with G
1 and has 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkenyl
group which is substituted with G
1 and has 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, an alkynyl
group which is substituted with G
1 and has 2 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, a cycloalkyl
group which is substituted with G
1 and has 3 to 8 carbon atoms, an alkylidene group having 1 to 6 carbon atoms, an alkylidene
group which is substituted with G
1 and has 1 to 6 carbon atoms, a formyl group, an alkylcarbonyl group having 1 to 6
carbon atoms, an alkylcarbonyl group which is substituted with G
1 and has 1 to 6 carbon atoms, a cycloalkylcarbonyl group having 3 to 8 carbon atoms,
a cycloalkylcarbonyl group which is substituted with G
1 and has 3 to 8 carbon atoms, an alkoxycarbonyl group having 1 to 6 carbon atoms,
an alkoxycarbonyl group which is substituted with G
1 and has 1 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, or
an alkylsulfonyl group which is substituted with G
1 and has 1 to 6 carbon atoms; R
2 represents an amino group, an amino group substituted with one G
2, an amino group substituted with two G
2s which are the same as or different from each other, a hydroxyl group, an alkoxy
group having 1 to 6 carbon atoms, an alkylcarbonyloxy group having 1 to 6 carbon atoms,
an alkoxycarbonyloxy group having 1 to 6 carbon atoms, a cyano group, or an alkyl
group which is substituted with G
3 and has 1 to 6 carbon atoms; G
3 represents an amino group, an amino group substituted with one G
2, an amino group substituted with two G
2s which are the same as or different from each other, a hydroxyl group, an alkoxy
group having 1 to 6 carbon atoms, an alkylcarbonyloxy group having 1 to 6 carbon atoms,
an alkoxycarbonyloxy group having 1 to 6 carbon atoms, or a cyano group; a represents
an integer of 1 to 4, and when a represents 2 or greater, R
2s may be the same as or different from each other; R
3 represents a halogen atom or an organic group other than G
3; b represents an integer of 0 to 3, and when b represents 2 or greater, R
3s may be the same as or different from each other, provided that a relationship of
"a + b ≤ 4" is satisfied; R
4 represents a cyano group or an alkyl group which is substituted with G
3 and has 1 to 6 carbon atoms; c represents an integer of 0 to 3, and when c represents
2 or greater, R
4s may be the same as or different from each other; R
5 represents a halogen atom or an organic group other than G
3; d represents an integer of 0 to 3, and when d represents 2 or greater, R
5s may be the same as or different from each other, provided that a relationship of
"c + d ≤ 3" is satisfied; R
6 represents an alkyl group having 1 to 6 carbon atoms; and n represents an integer
of 0 to 4, and when n represents 2 or greater, R
6s may be the same as or different from each other and two R
6s may be bonded to each other to form an alkylene group having 2 to 6 carbon atoms.)
[0015] (In Formula (II), B
2 represents a group represented by NR
1c-COR
1a, a group represented by NR
1c-C(R
1a)=NOH, or a group represented by NR
1c-SO
2R
1b; R
1c represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; A, R
1a, R
1b, R
2, a, R
3, b, R
4, c, R
5, d, and R
6 have the same definitions as those in Formula (I); m represents an integer of 0 to
3, and when m represents 2 or greater, R
6s may be the same as or different from each other and two R
6s may be bonded to each other to form an alkylene group having 2 to 6 carbon atoms.)
[0016]
[2] The phenylimidazole derivative according to [1] or a salt thereof, wherein, in
Formula (I), A represents a nitrogen atom; B1 represents a group represented by N-COR1a; and the imidazolyl group which is a substituent of the benzene ring is an imidazole-1-yl
group.
[3] The phenylimidazole derivative according to [1] or a salt thereof, wherein, in
Formula (I), A represents a nitrogen atom; B1 represents a group represented by N-COR1a; the imidazolyl group which is a substituent of the benzene ring is an imidazole-1-yl
group; and the imidazolyl group is in a meta-position with respect to a piperazine
ring.
[4] The phenylimidazole derivative according to [1] or a salt thereof, wherein, in
Formula (II), A represents a nitrogen atom; B2 represents a group represented by NR1c-COR1a; and the imidazolyl group which is a substituent of the benzene ring is an imidazole-1-yl
group.
[5] The phenylimidazole derivative according to [1] or a salt thereof, wherein, in
Formula (II), A represents a nitrogen atom; B2 represents a group represented by NR1c-COR1a; the imidazolyl group which is a substituent of the benzene ring is an imidazole-1-yl
group; and the imidazolyl group is in a meta-position with respect to a pyrrolidine
ring.
[6] A therapeutic medicine or preventive medicine for inflammatory diseases, diseases
caused by lipid oxidation, or retinochoroidal disorders, the medicine comprising at
least one selected from the phenylimidazole derivative according to anyone of [1]
to [5], a salt thereof, and metabolites thereof, as an active ingredient.
[7] The therapeutic medicine or preventive medicine according to [6], further comprising
a pharmacologically acceptable additive.
[8] The therapeutic medicine or preventive medicine according to [6], wherein the
retinochoroidal disorder is age-related macular degeneration, diabetic retinopathy,
or diabetic macular edema.
[9] Use of at least one selected from the phenylimidazole derivative according to
any one of [1] to [5] and a salt thereof for treating or preventing inflammatory diseases,
diseases caused by lipid oxidation, or retinochoroidal disorders. Advantageous Effects
of Invention
[0017] Since a phenylimidazole derivative of the present invention and a salt thereof inhibits
respective enzyme activities of leukotriene A4 hydrolase, leukotriene C4 synthase,
thromboxane synthase, phospholipase A2-II, and MAP kinase I, the phenylimidazole derivative
or a salt thereof is useful as an active ingredient of therapeutic medicine or preventive
medicine for various inflammatory diseases. In addition, since the phenylimidazole
derivative or a salt thereof inhibits activities of 15-lipoxygenase and lipid peroxidase,
the phenylimidazole derivative or a salt thereof is useful as an active ingredient
of therapeutic medicine or preventive medicine for various diseases caused by lipid
oxidation.
[0018] Further, since the phenylimidazole derivative of the present invention or a salt
thereof exhibits effects of a treatment or prevention of retinochoroidal disorders,
particularly, retinal light disorders, the phenylimidazole derivative or a salt thereof
is useful as an active ingredient of therapeutic medicine or preventive medicine of
retinal light disorders.
[0019] The therapeutic medicine or preventive medicine according to the present invention
is expected to exhibit therapeutic effect or preventive effect for retinal light disorders,
with maintaining excellent tissue migration properties by oral administration.
Brief Description of Drawings
[0020]
FIG. 1 is a view showing a horizontal meridian section of an eye.
FIG. 2 is a view showing a posterior pole of an eye.
FIG. 3 is a view showing each layer of optic part of retina.
Description of Embodiments
[0021] Aphenylimidazole derivative is a compound represented by Formula (I) or (II). Further,
a salt of the phenylimidazole derivative is a salt of the compound represented by
Formula (I) or (II).
[A, B1, B2]
[0022]
A in Formula (I) or (II) represents a carbon atom or a nitrogen atom.
B1 in Formula (I) represents a carbonyl group, a group represented by N-COR1a, a group represented by N-C(R1a)=NOH, or a group represented by N-SO2R1b. Among these, a group represented by N-COR1a is preferable.
B2 in Formula (II) represents a group represented by NR1c-COR1a, a group represented by NR1c-C(R1a)=NOH, or a group represented by NR1c-SO2R1b. Among these, a group represented by NR1c-COR1a is preferable.
[0023] R
1a in B
1 or B
2 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkyl group
which is substituted with G
1 and has 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkenyl
group which is substituted with G
1 and has 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, an alkynyl
group which is substituted with G
1 and has 2 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, a cycloalkyl
group which is substituted with G
1 and has 3 to 8 carbon atoms, a hydroxyl group, an alkoxy group having 1 to 6 carbon
atoms, an alkoxy group which is substituted with G
1 and has 1 to 6 carbon atoms, an alkenyloxy group having 2 to 6 carbon atoms, an alkenyloxy
group which is substituted with G
1 and has 2 to 6 carbon atoms, an alkynyloxy group having 2 to 6 carbon atoms, an alkynyloxy
group which is substituted with G
1 and has 2 to 6 carbon atoms, an amino group, an amino group substituted with one
G
2, or an amino group substituted with two G
2s which are the same as or different from each other. Here, in this case where the
amino group is substituted with two G
2s, two G
2s may be bonded to each other to form a ring.
[0024] R
1b in B
1 or B
2 represents an alkyl group having 1 to 6 carbon atoms, an alkyl group which is substituted
with G
1 and has 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkenyl
group which is substituted with G
1 and has 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, an alkynyl
group which is substituted with G
1 and has 2 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, a cycloalkyl
group which is substituted with G
1 and has 3 to 8 carbon atoms, a hydroxyl group, an alkoxy group having 1 to 6 carbon
atoms, an alkoxy group which is substituted with G
1 and has 1 to 6 carbon atoms, an alkenyloxy group having 2 to 6 carbon atoms, an alkenyloxy
group which is substituted with G
1 and has 2 to 6 carbon atoms, an alkynyloxy group having 2 to 6 carbon atoms, an alkynyloxy
group which is substituted with G
1 and has 2 to 6 carbon atoms, an amino group, an amino group substituted with one
G
2, or an amino group substituted with two G
2s which are the same as or different from each other. Here, in a case where the amino
group is substituted with two G
2s, two G
2s may be bonded to each other to form a ring.
[0025] R
1C in B
2 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
[0026] G
1 in R
1a and R
1b represents a halogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon
atoms, an amino group, or an amino group substituted with an alkyl group having 1
to 6 carbon atoms.
[0027] Examples of the "halogen atom" in G
1 include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
[0028] Examples of the "alkoxy group having 1 to 6 carbon atoms" in G
1 include a methoxy group, an ethoxy group, a n-propoxy group, a n-butoxy group, a
n-pentyloxy group, a n-hexyloxy group, an i-propoxy group, an i-butoxy group, a s-butoxy
group, a t-butoxy group, and an i-hexyloxy group.
[0029] Examples of the "amino group substituted with an alkyl group having 1 to 6 carbon
atoms" in G
1 include a methylamino group, a dimethylamino group, and a diethylamino group.
[0030] G
2 in R
1a and R
1b represents an alkyl group having 1 to 6 carbon atoms, an alkyl group which is substituted
with G
1 and has 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkenyl
group which is substituted with G
1 and has 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, an alkynyl
group which is substituted with G
1 and has 2 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, a cycloalkyl
group which is substituted with G
1 and has 3 to 8 carbon atoms, an alkylidene group having 1 to 6 carbon atoms, an alkylidene
group which is substituted with G
1 and has 1 to 6 carbon atoms, a formyl group, an alkylcarbonyl group having 1 to 6
carbon atoms, an alkylcarbonyl group which is substituted with G
1 and has 1 to 6 carbon atoms, a cycloalkylcarbonyl group having 3 to 8 carbon atoms,
a cycloalkylcarbonyl group which is substituted with G
1 and has 3 to 8 carbon atoms, an alkoxycarbonyl group having 1 to 6 carbon atoms,
an alkoxycarbonyl group which is substituted with G
1 and has 1 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, or
an alkylsulfonyl group which is substituted with G
1 and has 1 to 6 carbon atoms. G
1 is the same as defined above and examples thereof include the same as those described
above for G
1.
[0031] Examples of the "alkyl group having 1 to 6 carbon atoms" in G
2 include a methyl group, an ethyl group, a n-propyl group, a n-butyl group, a n-pentyl
group, a n-hexyl group, an i-propyl group, an i-butyl group, a s-butyl group, a t-butyl
group, an i-pentyl group, a neopentyl group, a 2-methylbutyl group, a 2,2-dimethylpropyl
group, and an i-hexyl group.
[0032] Examples of the "alkyl group which is substituted with G
1 and has 1 to 6 carbon atoms" in G
2 include a haloalkyl group having 1 to 6 carbon atoms such as a fluoromethyl group,
a chloromethyl group, a bromomethyl group, a difluoromethyl group, a dichloromethyl
group, a dibromomethyl group, a trifluoromethyl group, a trichloromethyl group, a
tribromomethyl group, a 2,2,2-trifluoroethyl group, or a 2,2,2-trichloroethyl group;
a hydroxy C1 to C6 alkyl group such as a hydroxymethyl group or a 2-hydroxyethyl group;
a C1 to C6 alkoxy C1 to C6 alkyl group such as a methoxymethyl group, an ethoxymethyl
group, a methoxyethyl group, an ethoxyethyl group, a methoxy-n-propyl group, a n-propoxymethyl
group, an i-propoxyethyl group, a s-butoxymethyl group, or a t-butoxyethyl group;
an amino C1 to C6 alkyl group such as an amino methyl group or an aminoethyl group;
and a C1 to C6 alkylamino C1 to C6 alkyl group such as a methylaminomethyl group,
an ethylaminomethyl group, a dimethylaminomethyl group or a diethylaminomethyl group.
[0033] Examples of the "alkenyl group having 2 to 6 carbon atoms" in G
2 include a vinyl group, a 1-propenyl group, a 2-propenyl group, a 1-butenyl group,
a 2-butenyl group, a 3-butenyl group, a 1-methyl-2-propenyl group, a 2-methyl-2-propenyl
group, a 1-pentenyl group, a 2-pentenyl group, a 3-pentenyl group, a 4-pentenyl group,
a 1-methyl-2-butenyl group, a 2-methyl-2-butenyl group, a 1-hexenyl group, a 2-hexenyl
group, a 3-hexenyl group, a 4-hexenyl group, and a 5-hexenyl group.
[0034] Examples of the "alkenyl group which is substituted with G
1 and has 2 to 6 carbon atoms" in G
2 include a haloalkenyl group having 2 to 6 carbon atoms such as a 2-chloro-1-propenyl
group or a 2-fluoro-1-butenyl group; a hydroxy C2 to C6 alkenyl group such as a 2-hydroxy-1-propenyl
group or a 2-hydroxy-1-butenyl group; a C1 to C6 alkoxy C2 to C6 alkenyl group such
as a 2-methoxy-1-propenyl group or a 2-methoxy-1-butenyl group; an amino C2 to C6
alkenyl group such as a 2-amino-1-propenyl group or a 2-amino-1-butenyl group; and
a C1 to C6 alkylamino C2 to C6 alkenyl group such as a 2-methylamino-1-propenyl group
or a 2-dimethylamino-1-butenyl group.
[0035] Examples of the "alkynyl group having 2 to 6 carbon atoms" in G
2 include an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group,
a 2-butynyl group, a 3-butynyl group, a 1-methyl-2-propynyl group, a 2-methyl-3-butynyl
group, a 1-pentynyl group, a 2-pentynyl group, a 3-pentynyl group, a 4-pentynyl group,
a 1-methyl-2-butynyl group, a 2-methyl-3-pentynyl group, a 1-hexynyl group, and a
1,1-dimethyl-2-butynyl group.
[0036] Examples of the "alkynyl group which is substituted with G
1 and has 2 to 6 carbon atoms" in G
2 include a haloalkynyl group having 2 to 6 carbon atoms such as a 4,4-dichloro-1-butynyl
group, a 4-fluoro-1-pentynyl group, or a 5-bromo-2-pentynyl group; a hydroxy C2 to
C6 alkynyl group such as a 4-hydroxy-1-pentynyl group or a 5-hydroxy-2-pentynyl group;
a C1 to C6 alkoxy C2 to C6 alkynyl group such as a 4-methoxy-1-pentynyl group or a
5-methoxy-2-pentynyl group; an amino C2 to C6 alkynyl group such as a 4-amino-1-pentynyl
group or a 5-amino-2-pentynyl group; and a C1 to C6 alkylamino C2 to C6 alkynyl group
such as a 4-methylamino-1-pentynyl group or a 5-dimethylamino-2-pentynyl group.
[0037] Examples of the "cycloalkyl group having 3 to 8 carbon atoms" in G
2 include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl
group, and a cycloheptyl group.
[0038] Examples of the "cycloalkyl group which is substituted with G
1 and has 3 to 8 carbon atoms" in G
2 include a halo C3 to C8 cycloalkyl group such as a 1-chloro-cyclopropyl group, a
1-chloro-cyclobutyl group, or a 3,3,4,4-tetrafluoro-cyclopentyl group; a hydroxy C3
to C8 cycloalkyl group such as a 1-hydroxy-cyclopropyl group or a 1-hydroxy-cyclobutyl
group; a C1 to C6 alkoxy C3 to C8 cycloalkyl group such as a 1-methoxy-cyclopropyl
group, a 1-methoxy-cyclobutyl group, or a 3,4-dimethoxy-cyclopentyl group; an amino
C3 to C8 cycloalkyl group such as a 1-amino-cyclopropyl group, a 1-amino-cyclobutyl
group, or a 3-amino-cyclopentyl group; and a C1 to C6 alkylamino C3 to C8 cycloalkyl
group such as a 1-methylamino-cyclopropyl group, a 1-dimethylamino-cyclobutyl group,
or a 3-dimethylamino-cyclopentyl group.
[0039] Examples of the "alkylidene group having 1 to 6 carbon atoms" in G
2 include a methylidene group, an ethylidene group, or a propylidene group.
[0040] Examples of the "alkylidene group which is substituted with G
1 and has 1 to 6 carbon atoms" in G
2 include a haloalkylidene group having 1 to 6 carbon atoms such as a 1-chloro-methylidene
group, a 2-chloro-ethylidene group, or a 3,3,3-trifluoro-propylidene group; a hydroxy
C1 to C6 alkylidene group such as a 1-hydroxy-methylidene group, a 2-hydroxy-ethylidene
group, or a 3-hydroxy-propylidene group; a C1 to C6 alkoxy C1 to C6 alkylidene group
such as a 1-methoxy-methylidene group, a 2-methoxy-ethylidene group, or a 3-methoxy-propylidene
group; an amino C1 to C6 alkylidene group such as a 1-amino-methylidene group, a 2-amino-ethylidene
group, or a 3-amino-propylidene group; and a C1 to C6 alkylamino C1 to C6 alkylidene
group such as a 1-methylamino-methylidene group, a 2-dimethylamino-ethylidene group,
or a 3-ethylamino-propylidene group.
[0041] Examples of the "alkylcarbonyl group having 1 to 6 carbon atoms" in G
2 include an acetyl group and a propionyl group.
[0042] Examples of the "alkylcarbonyl group which is substituted with G
1 and has 1 to 6 carbon atoms" in G
2 include a haloalkylcarbonyl group having 1 to 6 carbon atoms such as a chloroacetyl
group, a trifluoroacetyl group, or a trichloroacetyl group; a hydroxy C1 to C6 alkylcarbonyl
group such as a hydroxyacetyl group or a 2-hydroxypropionyl group; a C1 to C6 alkoxy
C1 to C6 alkylcarbonyl group such as a methoxyacetyl group, an ethoxyacetyl group,
a methoxypropionyl group, an ethoxypropionyl group, an ethoxyacetyl group, an ethoxypropionyl
group, a n-propoxyacetyl group, an i-propoxypropionyl group, a s-butoxyacetyl group,
or a t-butoxypropionyl group; an amino C1 to C6 alkylcarbonyl group such as an aminoacetyl
group or an aminopropionyl group; and a C1 to C6 alkylamino C1 to C6 alkylcarbonyl
group such as a methylaminoacetyl group, an ethylaminoacetyl group, a dimethylaminoacetyl
group, or a diethylaminoacetyl group.
[0043] Examples of the "cycloalkylcarbonyl group having 3 to 8 carbon atoms" in G
2 include a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, and a cyclopentylcarbonyl
group.
[0044] Examples of the "cycloalkylcarbonyl group which is substituted with G
1 and has 3 to 8 carbon atoms" in G
2 include a halo C3 to C8 cycloalkylcarbonyl group such as a 1-chloro-cyclopropylcarbonyl
group, a 1-chloro-cyclobutylcarbonyl group, or a 3,3,4,4-tetrafluoro-cyclopentylcarbonyl
group; a hydroxy C3 to C8 cycloalkylcarbonyl group such as a 1-hydroxy-cyclopropylcarbonyl
group or a 1-hydroxy-cyclobutylcarbonyl group; a C1 to C6 alkoxy C3 to C8 cycloalkylcarbonyl
group such as a 1-methoxy-cyclopropylcarbonyl group, a 1-methoxy-cyclobutylcarbonyl
group, or a 3,4-dimethoxy-cyclopentylcarbonyl group; an amino C3 to C8 cycloalkylcarbonyl
group such as a 1-amino-cyclopropylcarbonyl group, a 1-amino-cyclobutylcarbonyl group,
or a 3-amino-cyclopentylcarbonyl group; and a C1 to C6 alkylamino C3 to C8 cycloalkylcarbonyl
group such as a 1-methylamino-cyclopropylcarbonyl group, a 1-dimethylamino-cyclobutylcarbonyl
group, or a 3-dimethylamino-cyclopentylcarbonyl group.
[0045] Examples of the "alkoxycarbonyl group having 1 to 6 carbon atoms" in G
2 include a methoxycarbonyl group, an ethoxycarbonyl group, a n-propoxycarbonyl group,
and an i-propoxycarbonyl group.
[0046] Examples of the "alkoxycarbonyl group which is substituted with G
1 and has 1 to 6 carbon atoms" in G
2 include a haloalkoxycarbonyl group having 1 to 6 carbon atoms such as a fluoromethoxycarbonyl
group, a chloromethoxycarbonyl group, a bromomethoxycarbonyl group, a difluoromethoxycarbonyl
group, a dichloromethoxycarbonyl group, a dibromomethoxycarbonyl group, a trifluoromethoxycarbonyl
group, a trichloromethoxycarbonyl group, a tribromomethoxycarbonyl group, a 2,2,2-trifluoroethoxycarbonyl
group, or a 2,2,2-trichloroethoxycarbonyl group; a hydroxy C1 to C6 alkoxycarbonyl
group such as a hydroxymethoxycarbonyl group or a 2-hydroxyethoxycarbonyl group; a
C1 to C6 alkoxy C1 to C6 alkoxycarbonyl group such as a methoxymethoxycarbonyl group,
an ethoxymethoxycarbonyl group, a methoxyethoxycarbonyl group, an ethoxyethoxycarbonyl
group, a methoxy-n-propoxycarbonyl group, a n-propoxymethoxycarbonyl group, an i-propoxyethoxycarbonyl
group, a s-butoxymethoxycarbonyl group, or a t-butoxyethoxycarbonyl group; an amino
C1 to C6 alkoxycarbonyl group such as an aminomethoxycarbonyl group or an aminoethoxycarbonyl
group; and a C1 to C6 alkylamino C1 to C6 alkoxycarbonyl group such as a methylamino
methoxycarbonyl group, an ethylamino methoxycarbonyl group, a dimethylamino methoxycarbonyl
group, or a diethylamino methoxycarbonyl group.
[0047] Examples of the "alkylsulfonyl group having 1 to 6 carbon atoms" in G
2 include a methylsulfonyl group, an ethylsulfonyl group, and a t-butylsulfonyl group.
[0048] Examples of the "alkylsulfonyl group which is substituted with G
1 and has 1 to 6 carbon atoms" in G
2 include a haloalkylsulfonyl group having 1 to 6 carbon atoms such as a fluoromethylsulfonyl
group, a chloromethylsulfonyl group, a bromomethylsulfonyl group, a difluoromethylsulfonyl
group, a dichloromethylsulfonyl group, a dibromomethylsulfonyl group, a trifluoromethylsulfonyl
group, a trichloromethylsulfonyl group, a tribromomethylsulfonyl group, a 2,2,2-trifluoroethylsulfonyl
group, or a 2,2,2-trichloroethylsulfonyl group; a hydroxy C 1 to C6 alkylsulfonyl
group such as a hydroxymethylsulfonyl group or a 2-hydroxyethylsulfonyl group; a C1
to C6 alkoxy C1 to C6 alkylsulfonyl group such as a methoxymethylsulfonyl group, an
ethoxymethylsulfonyl group, a methoxyethylsulfonyl group, an ethoxyethylsulfonyl group,
a methoxy-n-propylsulfonyl group, a n-propoxymethylsulfonyl group, an i-propoxyethylsulfonyl
group, a s-butoxymethylsulfonyl group, or a t-butoxyethyl group; an amino C1 to C6
alkylsulfonyl group such as an aminomethylsulfonyl group or an aminoethylsulfonyl
group; and a C1 to C6 alkylamino C1 to C6 alkylsulfonyl group such as a methylamino
methylsulfonyl group, an ethylamino methylsulfonyl group, a dimethylamino methylsulfonyl
group, or a diethylamino methylsulfonyl group.
[0049] As the "alkyl group having 1 to 6 carbon atoms," the "alkyl group which is substituted
with G
1 and has 1 to 6 carbon atoms," the "alkenyl group having 2 to 6 carbon atoms," the
"alkenyl group which is substituted with G
1 and has 2 to 6 carbon atoms," the "alkynyl group having 2 to 6 carbon atoms," the
"alkynyl group which is substituted with G
1 and has 2 to 6 carbon atoms," the "cycloalkyl group having 3 to 8 carbon atoms,"
and the "cycloalkyl group which is substituted with G
1 and has 3 to 8 carbon atoms" in R
1a and R
1b the same groups as described above in G
2 are exemplary examples.
[0050] As the "alkoxy group having 1 to 6 carbon atoms" in R
1a and R
1b, the same groups as described above in the "alkoxy group having 1 to 6 carbon atoms"
in G
1 are exemplary examples.
[0051] Examples of the "alkoxy group which is substituted with G
1 and has 1 to 6 carbon atoms" in R
1a and R
1b include a haloalkoxy group having 1 to 6 carbon atoms such as a fluoromethoxy group,
a chloromethoxy group, a bromomethoxy group, a difluoromethoxy group, a dichloromethoxy
group, a dibromomethoxy group, a trifluoromethoxy group, a trichloromethoxy group,
a tribromomethoxy group, a 2,2,2-trifluoroethoxy group, or a 2,2,2-trichloroethoxy
group; a hydroxy C1 to C6 alkoxy group such as a hydroxymethoxy group or a 2-hydroxyethoxy
group; a C1 to C6 alkoxy C1 to C6 alkoxy group such as a methoxymethoxy group, an
ethoxymethoxy group, a methoxyethoxy group, an ethoxyethoxy group, a methoxy-n-propoxy
group, a n-propoxymethoxy group, an i-propoxyethoxy group, a s-butoxymethoxy group,
or a t-butoxyethoxy group; an amino C1 to C6 alkoxy group such as an aminomethoxy
group or an aminoethoxy group; and a C1 to C6 alkylamino C1 to C6 alkoxy group such
as a methylaminomethoxy group, an ethylaminomethoxy group, a dimethylaminomethoxy
group, or a diethylaminomethoxy group.
[0052] Examples of the "alkenyloxy group having 2 to 6 carbon atoms" in R
1a and R
1b include an ethenyloxy group, a 1-methyl-2-propenyloxy group, and a 2-methyl-1-propenyloxy
group.
[0053] Examples of the "alkenyloxy group which is substituted with G
1 and has 2 to 6 carbon atoms" in R
1a and R
1b include a haloalkenyloxy group having 2 to 6 carbon atoms such as a 2-chloro-1-propenyloxy
group or a 2-fluoro-1-butenyloxy group; a hydroxy C2 to C6 alkenyloxy group such as
a 2-hydroxy-1-propenyloxy group or a 2-hydroxy-1-butenyloxy group; a C1 to C6 alkoxy
C2 to C6 alkenyloxy group such as a 2-methoxy-1-propenyloxy group or a 2-methoxy-1-butenyl
group; an amino C2 to C6 alkenyloxy group such as a 2-amino-1-propenyloxy group or
a 2-amino-1-butenyloxy group; and a C1 to C6 alkylamino C2 to C6 alkenyloxy group
such as a 2-methylamino-1-propenyloxy group or a 2-dimethylamino-1-butenyloxy group.
[0054] Examples of the "alkynyloxy group having 2 to 6 carbon atoms" in R
1a and R
1b include an ethynyloxy group, a propargyloxy group, a 1-methylpropargyloxy group,
and a 2-butynyloxy group.
[0055] Examples of the "alkynyloxy group which is substituted with G
1 and has 2 to 6 carbon atoms in R
1a and R
1b include a haloalkynyloxy group having 2 to 6 carbon atoms such as a 4,4-dichloro-1-butynyloxy
group, a 4-fluoro-1-pentynyloxy group, or a 5-bromo-2-pentynyloxy group; a hydroxy
C2 to C6 alkynyloxy group such as a 4-hydroxy-1-pentynyloxy group or a 5-hydroxy-2-pentynyloxy
group; a C1 to C6 alkoxy C2 to C6 alkynyloxy group such as a 4-methoxy-1-pentynyloxy
group or a 5-methoxy-2-pentynyloxy group; an amino C2 to C6 alkynyloxy group such
as a 4-amino-1-pentynyloxy group or a 5-amino-2-pentynyloxy group; a C1 to C6 alkylamino
C2 to C6 alkynyloxy group such as a 4-methylamino-1-pentynyloxy group or a 5-dimethylamino-2-pentynyloxy
group.
[0056] Examples of the "amino group substituted with one G
2" in R
1a and R
1b include an "alkylamino group having 1 to 6 carbon atoms" such as a methylamino group,
an ethylamino group, a n-propylamino group, or a n-butylamino group; an "alkenylamino
group having 2 to 6 carbon atoms" such as a vinylamino group, a 1-propenylamino group,
a 2-propenylamino group, or a 1-butenylamino group; an "alkynylamino group having
2 to 6 carbon atoms" such as an ethynylamino group, a 1-propynylamino group, a 2-propynylamino
group, a 1-butynylamino group, or a 2-butynylamino group; a "cycloalkylamino group
having 3 to 8 carbon atoms" such as a cyclopropylamino group, a cylobutylamino group,
a cyclopentylamino group, or a cyclohexylamino group; an "alkylideneamino group having
1 to 6 carbon atoms" such as a methylene amino group, an ethylideneamino group, or
a propylideneamino group; an "alkylcarbonylamino group having 1 to 6 carbon atoms"
such as an acetylamino group or a propionylamino group; a "cycloalkylcarbonylamino
group having 3 to 8 carbon atoms" such as a cyclopropylcarbonylamino group, a cyclobutylcarbonylamino
group, or a cyclopentylcarbonylamino group; an "alkoxycarbonylamino group having 1
to 6 carbon atoms" such as a methoxycarbonylamino group, an ethoxycarbonylamino group,
a n-propoxycarbonylamino group, or an i-propoxycarbonylamino group; and an "alkylsulfonylamino
group having 1 to 6 carbon atoms" such as a methylsulfonylamino group, an ethylsulfonylamino
group, or a t-butylsulfonylamino group.
[0057] Examples of the "amino group substituted with two G
2s which are the same as or different from each other" in R
1a and R
1b include a "di-C1 to C6 alkylamino group" such as a dimethylamino group, an ethyl-methyl-amino
group, a n-propyl-methyl-amino group, or a n-butyl-methyl-amino group; a "C2 to C6
alkenyl-(C1 to C6 alkyl)amino group" such as a vinyl-methyl-amino group, a 1-propenyl-methyl-amino
group, a 2-propenyl-methyl-amino group, or a 1-butenyl-methyl-amino group; a "C2 to
C6 alkynyl-(C1 to C6 alkyl)amino group" such as an ethynyl-methyl-amino group, a 1-propynyl-methyl-amino
group, a 2-propyl-methyl-amino group, a 1-butynyl-methyl-amino group, or a 2-butynyl-methyl-amino
group; a "C3 to C8 cycloalkyl-(C1-C6 alkyl)amino group" such as a cyclopropyl-methyl-amino
group, a cyclobutyl-methyl-amino group, a cyclopentyl-methyl-amino group, or a cyclohexyl-methyl-amino
group; a "C1 to C6 alkylcarbonyl-(C1 to C6 alkyl)amino group" such as an acetyl-methyl-amino
group, or a propionyl-methyl-amino group; a "C3 to C8 cycloalkylcarbonyl-(C1 to C6
alkyl)amino group" such as a cyclopropylcarbonyl-methyl-amino group, a cyclobutylcarbonyl-methyl-amino
group, or a cyclopentylcarbonyl-methyl-amino group; a "C1 to C6 alkoxycarbonyl-(C1
to C6 alkyl)amino group" such as a methoxycarbonyl-methyl-amino group, an ethoxycarbonyl-methyl-amino
group, a n-propoxycarbonyl-methyl-amino group, or an i-propoxycarbonyl-methyl-amino
group; and a "C1 to C6 alkylsulfonyl-(C1 to C6 alkyl)amino group such as a methylsulfonyl-methyl-amino
group, an ethylsulfonyl-methyl-amino group, or a t-butylsulfonyl-methyl-amino group.
[0058] In addition, examples of the "the ring formed by an amino group being substituted
with two G
2s and the two G
2s being bonded to each other" include saturated heterocyclic groups such as an aziridine
ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, and a morpholine ring.
[0059] As the "alkyl group having 1 to 6 carbon atoms" in R
1c, the same groups as described above in G
2 are exemplary examples.
[R2]
[0060] R
2 represents an amino group, an amino group substituted with one G
2, an amino group substituted with two G
2s which are the same as or different from each other, a hydroxyl group, an alkoxy
group having 1 to 6 carbon atoms, an alkylcarbonyloxy group having 1 to 6 carbon atoms,
an alkoxycarbonyloxy group having 1 to 6 carbon atoms, a cyano group, or an alkyl
group which is substituted with G
3 and has 1 to 6 carbon atoms. a represents an integer of 1 to 4, and when a represents
2 or greater, R
2s may be the same as or different from each other.
[0061] G
2 in R
2 has the same definition as that for G
2 in R
1a and R
1b and examples thereof are the same as those exemplified above in the description of
R
1a and R
1b.
[0062] As the "amino group substituted with one G
2" and the "amino group substituted with two G
2s which are the same as or different from each other" in R
2, the same as groups described above in R
1a are exemplary examples. As the "alkoxy group having 1 to 6 carbon atoms" in R
2, the same as groups described above in G
1 are exemplary examples.
[0063] Examples of the "alkylcarbonyloxy group having 1 to 6 carbon atoms" in R
2 include an acetyloxy group and a propionyloxy group.
[0064] Examples of the "alkoxycarbonyloxy group having 1 to 6 carbon atoms" in R
2 include a methoxycarbonyloxy group and an ethoxycarbonyloxy group.
[0065] G
3 in R
2 represents an amino group, an amino group substituted with one G
2, an amino group substituted with two G
2s which are the same as or different from each other, a hydroxyl group, an alkoxy
group having 1 to 6 carbon atoms, an alkylcarbonyloxy group having 1 to 6 carbon atoms,
an alkoxycarbonyloxy group having 1 to 6 carbon atoms, or a cyano group. G
2 in G
3 has the same definition as that described above and examples thereof are the same
as those described above.
[0066] As the "amino group substituted with one G
2" and the "amino group substituted with two G
2s which are the same as or different from each other" in G
3, the same as groups described in R
1a are exemplary examples. As the "alkoxy group having 1 to 6 carbon atoms" in G
3, the same as groups described in G
1 are exemplary examples. As the "alkylcarbonyloxy group having 1 to 6 carbon atoms"
and the "alkoxycarbonyloxy group having 1 to 6 carbon atoms," the same as groups described
in R
2 are exemplary examples.
[0067] Examples of the "alkyl group which is substituted with G
3 and has 1 to 6 carbon atoms" in R
2 include an alkyl group which is substituted with an amino group and has 1 to 6 carbon
atoms, an alkyl group which is substituted with an amino group substituted with one
G
2 and has 1 to 6 carbon atoms, an alkyl group which is substituted with an amino group
substituted with two G
2s which are the same as or different from each other and has 1 to 6 carbon atoms;
an alkyl group which is substituted with a hydroxyl group and has 1 to 6 carbon atoms,
an alkyl group which is substituted with an alkoxy group having 1 to 6 carbon atoms
and has 1 to 6 carbon atoms, an alkyl group which is substituted with an alkylcarbonyloxy
group having 1 to 6 carbon atoms and has 1 to 6 carbon atoms, an alkyl group which
is substituted with an alkoxycarbonyloxy group having 1 to 6 carbon atoms and has
1 to 6 carbon atoms, and an alkyl group which is substituted with a cyano group and
has 1 to 6 carbon atoms.
[0068] Examples of the "alkyl group which is substituted with an amino group and has 1 to
6 carbon atoms" in R
2 include an aminomethyl group and an aminoethyl group.
[0069] Examples of the "alkyl group which is substituted with an amino group substituted
with one G
2 and has 1 to 6 carbon atoms" in R
2 include a "C1 to C6 alkylamino C1 to C6 alkyl group" such as a methylaminomethyl
group, an ethylaminomethyl group, a n-propylaminomethyl group, or a n-butylaminomethyl
group; a "C2 to C6 alkenylamino C1 to C6 alkyl group" such as a vinylaminomethyl group,
a 1-propenylaminomethyl group, a 2-propenylaminomethyl group, or a 1-butenylaminomethyl
group; a "C2 to C6 alkynylamino C1 to C6 alkyl group" such as an ethynylaminomethyl
group, a 1-propynylaminomethyl group, a 2-propylaminomethyl group, a 1-butynylaminomethyl
group, or a 2-butynylaminomethyl group; a "C3 to C8 cycloalkylamino C1 to C6 alkyl
group" such as a cyclopropylaminomethyl group, a cyclobutylaminomethyl group, a cyclopentylamino
group, or a cyclohexylaminomethyl group; a "C1 to C6 alkylideneamino C1 to C6 alkyl
group" such as a methylideneaminomethyl group, an ethylideneaminomethyl group, or
a propylideneaminomethyl group; a "C1 to C6 alkylcarbonylamino C1 to C6 alkyl group"
such as an acetylaminomethyl group or a propionylaminomethyl group; a "C3 to C8 cycloalkylcarbonylamino
C1 to C6 alkyl group" such as a cyclopropylcarbonylaminomethyl group, a cyclobutylcarbonylaminomethyl
group, or a cyclopentylcarbonylaminomethyl group; a "C1 to C6 alkoxycarbonylamino
C1 to C6 alkyl group" such as a methoxycarbonylaminomethyl group, an ethoxycarbonylaminomethyl
group, a n-propoxycarbonylaminomethyl group, or an i-propoxycarbonylaminomethyl group;
and a "C1 to C6 alkylsulfonylamino C1 to C6 alkyl group" such as a methylsulfonylaminomethyl
group, an ethylsulfonylaminomethyl group, or a t-butylsulfonylaminomethyl group.
[0070] Examples of the "alkyl group which is substituted with an amino group substituted
with two G
2s which are the same as or different from each other and has 1 to 6 carbon atoms"
in R
2 include a "di-C1 to C6 alkylamino C1 to C6 alkyl group" such as a dimethylaminomethyl
group, an ethyl-methyl-aminomethyl group, a n-propyl-methyl-aminomethyl group, or
a n-butyl-methyl-aminomethyl group; a "C2 to C6 alkenyl-(C1 to C6 alkyl) amino C1
to C6 alkyl group" such as a vinyl-methyl-aminomethyl group, a 1-propenyl-methyl-aminomethyl
group, a 2-propenyl-methyl-aminomethyl group, or a 1-butenyl-methyl-aminomethyl group;
a "C2 to C6 alkynyl-(C1 to C6 alkyl) amino C1 to C6 alkyl group" such as an ethynyl-methyl-aminomethyl
group, a 1-propynyl-methyl-aminomethyl group, a 2-propynyl-mehyl-aminomethyl group,
a 1-butynyl-methyl-aminomethyl group, or a 2-butynyl-methyl-aminomethyl group; a "C3
to C8 cycloalkyl-(C1 to C6 alkyl) amino C1 to C6 alkyl group" such as a cyclopropyl-methyl-aminomethyl
group, a cyclobutyl-methyl-aminomethyl group, a cyclopentyl-methyl-aminomethyl group,
or a cyclohexyl-methyl-aminomethyl group; a "C1 to C6 alkylcarbonyl-(C1 to C6 alkyl)
amino C1 to C6 alkyl group" such as an acetyl-methyl-aminomethyl group or a propionyl-methyl-aminomethyl
group; a "C3 to C8 cycloalkylcarbonyl-(C1 to C6 alkyl) amino C1 to C6 alkyl group"
such as a cyclopropylcarbonyl-methyl-aminomethyl group, a cyclobutylcarbonyl-methyl-aminomethyl
group, or a cyclopentylcarbonyl-methyl-aminomethyl group; a "C1 to C6 alkoxycarbonyl-(C1
to C6 alkyl) amino C1 to C6 alkyl group" such as a methoxycarbonyl-methyl-aminomethyl
group, an ethoxycarbonyl-methyl-aminomethyl group, a n-propoxycarbonyl-methyl-aminomethyl
group, or an i-propoxycarbonyl-methyl-aminomethyl group; and a "C1 to C6 alkylsulfonyl-(C1
to C6 alkyl) amino C1 to C6 alkyl group" such as a methylsulfonyl-methyl-aminomethyl
group, an ethylsulfonyl-methyl-aminomethyl group, or a t-butylsulfonyl-methyl-aminomethyl
group.
[0071] Examples of the "alkyl group which is substituted with a hydroxyl group and has 1
to 6 carbon atoms" in R
2 include a "hydroxy C1 to C6 alkyl group" such as a hydroxymethyl group or a 2-hydroxyethyl
group.
[0072] Examples of the "alkyl group which is substituted with an alkoxy group having 1 to
6 carbon atoms and has 1 to 6 carbon atoms" in R
2 include a "C1 to C6 alkoxy C1 to C6 alkyl group" such as a methoxymethyl group, an
ethoxymethyl group, a methoxyethyl group, an ethoxyethyl group, a methoxy-n-propyl
group, a n-propoxymethyl group, an i-propoxyethyl group, a s-butoxymethyl group, or
a t-butoxyethyl group.
[0073] Examples of the "alkyl group which is substituted with an alkylcarbonyloxy group
having 1 to 6 carbon atoms and has 1 to 6 carbon atoms" in R
2 include a "C1 to C6 alkylcarbonyloxy C1 to C6 alkyl group" such as an acetyloxymethyl
group or a propionyloxymethyl group.
[0074] Examples of the "alkyl group which is substituted with an alkoxycarbonyloxy group
having 1 to 6 carbon atoms and has 1 to 6 carbon atoms" in R
2 include a "C1 to C6 alkoxycarbonyloxy C1 to C6 alkyl group" such as a methoxycarbonyloxymethyl
group or an ethoxycarbonyloxymethyl group.
[0075] Examples of the "alkyl group which is substituted with a cyano group and has 1 to
6 carbon atoms" in R
2 include a "cyano C1 to C6 alkyl group" such as a cyanomethyl group or a 2-cyanoethyl
group.
[R3]
[0076] R
3 represents a halogen atom or an organic group other than G
3. G
3 in R
3 has the same definition as that described in R
2 and examples thereof are the same as those exemplified in the description above.
[0077] b indicates the number of R
3s and represents an integer of 0 to 3, and when b represents 2 or greater, R
3s may be the same as or different from each other provided that, a relationship of
"a + b ≤ 4" is satisfied.
[0078] Examples of the "organic group other than G
3" in R
3 include an arylamino group such as a benzylamino group, a phenylamino group, or a
phenylethylamino group, preferably an arylamino group having 6 to 10 carbon atoms;
a nitro group; a formyl group; an alkyl group having 1 to 6 carbon atoms such as a
methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group,
a s-butyl group, an isobutyl group, a t-butyl group, a n-pentyl group, or a n-hexyl
group; an alkenyl group having 2 to 6 carbon atoms such as a vinyl group or an allyl
group; an alkynyl group having 2 to 6 carbon atoms such as an ethynyl group, a 1-propynyl
group or a propargyl group; an alkenyloxy group having 2 to 6 carbon atoms such as
a vinyloxy group or an allyloxy group; an alkynyloxy group having 2 to 6 carbon atoms
such as an ethynyloxy group or a propargyloxy group; an aryloxy group such as a benzyloxy
group or a phenoxy group, preferably an aryloxy group having 6 to 10 carbon atoms;
a haloalkyl group having 1 to 6 carbon atoms such as a chloromethyl group, a fluoromethyl
group, a bromomethyl group, a dichloromethyl group, a difluoromethyl group, a dibromomethyl
group, a trichloromethyl group, a trifluoromethyl group, a bromodifluoromethyl group,
a 1,1,1-trifluoroethyl group, a 1-chloroethyl group, a 2-chloroethyl group, a 1-bromoethyl
group, or a pentafluoroethyl group; a haloalkoxy group having 1 to 6 carbon atoms
such as a fluoromethoxy group, a chloromethoxy group, a bromomethoxy group, a difluoromethoxy
group, a dichloromethoxy group, a dibromomethoxy group, a trifluoromethoxy group,
a trichloromethoxy group, a tribromomethoxy group, a trifluoroethoxy group, a pentafluoroethoxy
group, or a heptafluoro n-propoxy group; an alkylthiocarbonyl group having 1 to 6
carbon atoms such as a methylthiocarbonyl group, an ethylthiocarbonyl group, a n-propylthiocarbonyl
group, an isopropylthiocarbonyl group, a n-butylthiocarbonyl group, an isobutylthiocarbonyl
group, a s-butylthiocarbonyl group, or a t-butylthiocarbonyl group; an alkoxycarbonyl
group having 1 to 6 carbon atoms such as a methoxycarbonyl group, an ethoxycarbonyl
group, a n-propoxycarbonyl group, an isopropoxycarbonyl group, a n-butoxycarbonyl
group, or a t-butoxycarbonyl group; an aryl group such as a phenyl group, a 1-naphthyl
group, or a 2-naphthyl group, preferably an aryl group having 6 to 10 carbon atoms;
a 5-membered heteroaryl group such as a pyrrolyl group, a furyl group, a thienyl group,
an imidazolyl group, a pyrazolyl group, an oxazolyl group, an isoxazolyl group, a
thiazolyl group, an isothiazolyl group, a triazolyl group, an oxadiazolyl group, a
thiadiazolyl group, or a tetrazolyl group; a 6-membered heteroaryl group such as a
pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, or a triazinyl
group; a saturated heterocyclic group such as an aziridinyl group, an epoxy group,
a pyrrolidinyl group, a tetrahydrofuranyl group, a piperidyl group, a piperazinyl
group, or a morpholinyl group; an alkylthio group having 1 to 6 carbon atoms such
as a methylthio group, an ethylthio group, or a t-butylthio group; an alkylsulfonyl
group such as a methylsulfonyl group, an ethylsulfonyl group, or a t-butylsulfonyl
group; an alkenylsulfonyl group having 2 to 6 carbon atoms such as an allylsulfonyl
group; an alkynylsulfonyl group such as a propargylsulfonyl group, preferably an alkynylsulfonyl
group having 2 to 6 carbon atoms; an arylsulfonyl group such as a phenylsulfonyl group,
and preferably an arylsulfonyl group having 6 to 10 carbon atoms.
[R4]
[0079] R
4 represents a cyano group or an alkyl group which is substituted with G
3 and has 1 to 6 carbon atoms. c represents an integer of 0 to 3, and when c represents
2 or more, R
4s may be the same as or different from each other.
[0080] G
3 in R
4 has the same definition as that described in R
2 and examples thereof are the same as those exemplified in the description above.
[0081] Examples of the "alkyl group which is substituted with G
3 and has 1 to 6 carbon atoms" in R
4, the same as groups described in R
2 are exemplary examples.
[R5]
[0082] R
5 represents a halogen atom or an organic group other than G
3. d indicates the number of R
5S and represents an integer of 0 to 3, and when d represents 2 or more, R
5s may be the same as or different from each other, provided that, a relationship of
"c + d ≤ 3" is satisfied.
[0083] Examples of the organic groups other than G
3 in R
5 are the same as those described as the organic groups other than G
3 in R
3.
[R6]
[0084] R
6 represents an alkyl group having 1 to 6 carbon atoms.
n represents an integer of 0 to 4, and when n represents 2 or greater, R
6s may be the same as or different from each other and two R
6s may be bonded to each other to form an alkylene group having 2 to 6 carbon atoms.
m represents an integer of 0 to 3, and when m represents 2 or greater, R
6s may be the same as or different from each other and two R
6s may be bonded to each other to form an alkylene group having 2 to 6 carbon atoms.
[0085] As the "alkyl group having 1 to 6 carbon atoms" in R
6, the same as groups described in G
2 are exemplary examples.
[0086] As the "alkylene group having 2 to 6 carbon atoms" which is formed by R
6s being bonded to each other, an ethylene group or a propylene group is an exemplary
example.
[0087] In the phenylimidazole derivative of the present invention, it is preferable that,
in Formula (I), A represents a nitrogen atom, B
1 represents a group represented by N-COR
1a, and an imidazolyl group which is a substituent of the benzene ring is an imidazole-1-yl
group. That is, it is preferable that the phenylimidazole derivative of the present
invention is a phenylimidazole derivative represented by Formula (IA) or a salt thereof.
In Formula (IA), R
1a, R
2, R
3, R
4, R
5, R
6, a, b, c, d, and n are the same as those defined in Formula (I).
[0088] In the phenylimidazole derivative of the present invention, it is preferable that,
in Formula (I), A represents a nitrogen atom, B
1 represents a group represented by N-COR
1a, an imidazolyl group which is a substituent of the benzene ring is an imidazole-1-yl
group, and the imidazolyl group is in a meta-position with respect to a piperazine
ring. That is, it is preferable that the phenylimidazole derivative of the present
invention is a phenylimidazole derivative represented by Formula (IB) or a salt thereof.
In Formula (IB), R
1a, R
2, R
3, R
4, R
5, R
6, a, b, c, d, and n are the same as those defined in Formula (I).
[0089] In the phenylimidazole derivative of the present invention, it is preferable that,
in Formula (II), A represents a nitrogen atom, B
2 represents a group represented by NR
1c-COR
1a, and an imidazolyl group which is a substituent of the benzene ring is an imidazole-1-yl
group. That is, it is preferable that the phenylimidazole derivative of the present
invention is a phenylimidazole derivative represented by Formula (IIA) or a salt thereof.
In Formula (IIA), R
1a, R
1c, R
2, R
3, R
4, R
5, R
6, a, b, c, d, and m are the same as those defined in Formula (II).
[0090] In the phenylimidazole derivative of the present invention, it is preferable that,
in Formula (II), A represents a nitrogen atom, B
2 represents a group represented by NR
1c-COR
1a, an imidazolyl group which is a substituent of the benzene ring is an imidazole-1-yl
group, and the imidazolyl group be in a meta-position with respect to a pyrrolidine
ring. That is, it is preferable that the phenylimidazole derivative of the present
invention is a phenylimidazole derivative represented by Formula (IIB) or a salt thereof.
In Formula (IIB), R
1a, R
1c, R
2, R
3, R
4, R
5, R
6, a, b, c, d, and m have the same definitions as those described in Formula (II).
[0091] A salt of the phenylimidazole derivative is not particularly limited as long as the
salt is pharmacologically acceptable. Examples of such a salt include a salt of an
inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, or phosphoric
acid; and a salt of an organic acid such as acetic acid, oxalic acid, mandelic acid,
propionic acid, lactic acid, succinic acid, tartaric acid, citric acid, benzoic acid,
salicylic acid, nicotinic acid, hepta gluconic acid, methane sulfonic acid, benzene
sulfonic acid, or p-toluene sulfonic acid. A pharmacologically acceptable salt contains
an acid addition salt formed of a free amino group of a polypeptide or an antibody
molecule. These can be easily produced by a general chemically-synthesized method.
[0092] The phenylimidazole derivative of the present invention or a salt thereof includes
a geometric isomer, an optical isomer, or a tautomer. In addition, the phenylimidazole
derivative of the present invention or a salt thereof includes a hydrate or a solvate.
[0093] The phenylimidazole derivative of the present invention or a salt thereof includes
crystal polymorph and a crystal polymorphic group (crystal polymorphic system). In
addition, the crystal polymorphic group (crystal polymorphic system) indicates respective
crystal forms and the entire process in respective steps in a case where the crystal
form is changed due to the conditions and states (further, the present state also
includes a formulated state) such as production, crystallization, or storage of these
crystals.
[0094] A method of producing the phenylimidazole derivative of the present invention is
not particularly limited. For example, the phenylimidazole derivative can be produced
in the following manner.
[Production method 1]
[0095] A phenylimidazole derivative (a compound represented by Formula (6), hereinafter,
referred to as a compound (6)) in which, in Formula (I), A represents a nitrogen atom;
B
1 represents a group represented by N-COR
1a; an imidazolyl group is an imidazole-1-yl group; and R
2 represents an amino group can be produced by the following method.
[0096] A compound represented by Formula (3) (a, b, c, d, R
3, R
4, and R
5 in the formula are the same as those defined above in Formula (I). X represents a
halogen atom. Hereinafter, this compound is referred to as a compound (3)) can be
obtained by fusing a compound represented by Formula (1) (a, b, and R
3 in the formula are the same as those defined above in Formula (I). X represents a
halogen atom. Hereinafter, this compound is referred to as a compound (1)) and a compound
represented by Formula (2) (c, d, R
4, and R
5 in the formula are the same as those defined above in Formula (I). Hereinafter, this
compound is referred to as the compound (2)) in the presence of a base. The temperature
at the time of a condensation reaction is generally in the range of 0°C to a boiling
point of a solvent to be used.
[0097] In addition, a compound (a, b, c, d, n, R
1a, R
3, R
4, R
5, and R
6 in the formula are the same as those defined in Formula (I). Hereinafter, this compound
is referred to as a compound (5)) represented by Formula (5) can be obtained by fusing
the compound (3) and a compound (R
1a, R
6, and n in the formula are the same as those described in Formula (I). Hereinafter,
this compound is referred to as a compound (4)) represented by Formula (4) in the
presence of a base. The temperature at the time of a condensation reaction is generally
in the range of 0°C to a boiling point of a solvent to be used.
[0098] The base used for the condensation reaction of the compound (1) and the compound
(2) and the condensation reaction of the compound (3) and the compound (4), are not
particularly limited. Examples thereof include amines such as trimethylamine, pyridine,
and 1,8-diazabicyclo[5.4.0]undec-7-ene (hereinafter, referred to as "DBU") and inorganic
bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, and sodium
hydroxide.
[0099] The condensation reaction of the compound (1) and the compound (2) and the condensation
reaction of the compound (3) and the compound (4) can be performed in an appropriate
solvent. The solvent to be used is not particularly limited as long as the solvent
is inactive at the time of a reaction. Examples thereof include alcohols such as methanol
and ethanol; ethers such as diethyl ether, tetrahydrofuran, and 1,4-dioxane; hydrocarbons
such as benzene, toluene, xylene, and cyclohexane; amides such as N,N-dimethylformamide;
organic acids such as formic acid and acetic acid; esters such as ethyl acetate; and
a mixed solvent formed of two or more of these.
[0100] Next, a compound (6) (a, b, c, d, n, R
1a, R
3, R
4, R
5, and R
6 in the formula are the same as those defined in Formula (I)) can be obtained by reducing
the compound (5). The reduction reaction can be performed using a reducing agent or
a hydrogenation catalyst. Examples of the reduction reaction include a method of performing
reduction using hydrochloric acid and stannous chloride in an alcohol solvent such
as methanol or ethanol; a method of performing reduction using acetic acid and iron
in a mixed solvent of a ketone solvent such as acetone or methyl ethyl ketone and
water; a method of performing reduction using ammonium chloride, ammonium acetate,
ammonium formate, or acetic acid and zinc in alcohol or a mixed solvent of alcohol
and water; and a method of performing a hydrogenation reaction using a known hydrogenation
catalyst such as palladium carbon, palladium hydroxide, platinum dioxide, or Raney
nickel in alcohols such as methanol and ethanol; ethers such as diethyl ether, tetrahydrofuran,
and 1,4-dioxane; hydrocarbons such as benzene, toluene, xylene, and cyclohexane; amides
such as N,N-dimethylformamide and N,N-dimethylacetamide; organic acids such as formic
acid and acetic acid; esters such as ethyl acetate; or a mixed solvent formed of two
or more of these. The temperature at the time of a reduction reaction is normally
in the range of 0°C to a boiling point of a solvent to be used.
[Production method 2]
[0101] Aphenylimidazole derivative (a compound represented by Formula (6b)) in which A in
Formula (II) represents a nitrogen atom, B
2 represents a group represented by NR
1c-COR
1a, an imidazolyl group is an imidazole-1-yl group, and R
2 represents an amino group can be obtained in the same manner as in Production method
1, except that a compound (R
1a, R
1c, R
6, and m in the formula are the same as those defined in Formula (II)) represented
by Formula (4b) is used instead of the compound (4) used in Production method 1.
[Production method 3]
[0102] Aphenylimidazole derivative (a compound represented by Formula (15), hereinafter,
referred to as a compound (15)) in which A in Formula (I) represents a nitrogen atom,
B
1 represents a group represented by N-COR
1a, an imidazolyl group is an imidazole-1-yl group, and R
2 represents an amino group can be produced by the following method.
[0103] Zinc is inserted to a compound (R
6 and n in the formula are the same as those defined above) represented by Formula
(11) according to a method described in J. Org. Chem. 2004, 69, 5120 to induce a compound
(R
6 and n in the formula have the same definitions as those described above; hereinafter,
referred to as a compound (12)) represented by Formula (12) .
[0104] Next, a compound (R
6, n, a, b, and R
3 are the same as those defined above, hereinafter, referred to as a compound (13))
represented by Formula (13) can be obtained by performing a coupling reaction of the
compound (12) and the compound (1) using a palladium catalyst.
[0105] Examples of the palladium catalyst include bis(triphenylphosphine)palladium (II)
dichloride [PdCl
2(PPh
3)
2], palladium acetate [Pd(OAc)
2], tetrakistriphenylphosphine palladium (0) [Pd(PPh
3)
2], palladium (II) chloride [PdCl
2], tris(dibenzylidene acetone)dipalladium (0) [Pd
2(dba)
3], Pd/C, palladium-alumina, and [1,1'-bis(diphenylphosphine)-ferrocene]palladium II
dichlodride [PdCl
2(dppf)]. These catalysts can be used alone or in combination of two or more kinds
thereof In addition, a copper catalyst can be used together in the coupling reaction.
Examples of the copper catalyst include copper iodide (I), copper bromide (I), copper
chloride (I), and copper sulfate (II). These catalyst can be used alone or in combination
of two or more kinds thereof.
[0106] The reaction can be performed in an appropriate solvent. The solvent to be used is
not particularly limited as long as the solvent is inactive at the time of a reaction.
Examples thereof include ethers such as diethyl ether, tetrahydrofuran, and 1,4-dioxane;
hydrocarbons such as benzene, toluene, xylene, and cyclohexane; amides such as N,N-dimethylformamide
and N,N-dimethylacetamide; esters such as ethyl acetate; and a mixed solvent formed
of two or more of these.
[0107] Subsequently, a compound (a, b, c, d, n, R
1a, R
3, R
4, R
5, and R
6 in the formula are the same as those defined above, hereinafter, referred to as a
compound (14)) represented by Formula (14) can be obtained by fusing the compound
(13) and the compound (2) in the presence of a base. The condensation reaction can
be performed in the same manner as in Production method 1.
[0108] A compound (15) (a, b, c, d, n, R
1a, R
3, R
4, R
5, and R
6 in the formula are the same as those defined above) can be obtained by converting
structures of a tert-butoxycarbonyl (Boc) group and a nitro group in Formula (14)
by a conventional method.
[Production method 4]
[0109] Aphenylimidazole derivative (a compound represented by Formula (15b)) in which A
in Formula (II) represents a carbon atom, B
2 represents a group represented by NR
1c-COR
1a, an imidazolyl group is an imidazole-1-yl group, and R
2 represents an amino group can be obtained in the same manner as Production method
3, except that a compound represented by Formula (11b) (R
1c, R
6, and m in the formula are the same as those defined in Formula (II)) is used instead
of the compound (11) used in Production method 3.
[0110] The structure of the obtained compound can be identified and verified by measuring
such a spectrum using infrared spectroscopy, a nuclear magnetic resonance method,
or mass spectrometry.
[0111] Since the phenylimidazole derivative according to the present invention and a salt
thereof (hereinafter, also referred to as a compound of the present invention) inhibits
respective enzyme activities of leukotriene A4 hydrolase, leukotriene C4 synthase,
thromboxane synthase, phospholipase A2-II, and MAP kinase I, the phenylimidazole derivative
and a salt thereof can be used as an active ingredient of therapeutic medicine or
preventive medicine for various inflammatory diseases.
[0112] In addition, since the phenylimidazole derivative or a salt thereof inhibits activities
of 15-lipoxygenase and lipid peroxidase, the phenylimidazole derivative or a salt
thereof can be used as an active ingredient of therapeutic medicine or preventive
medicine for various diseases caused by lipid oxidation.
[0113] Further, since the compound of the present invention exhibits effects of a treatment
or prevention of retinochoroidal disorders, specifically, retinal light disorders,
the compound can be used as an active ingredient of therapeutic medicine or preventive
medicine for retinochoroidal disorders. More specifically, the compound of the present
invention can be used for treatment or prevention of retinochroidal diseases accompanied
by retinochoroidal disorders, for example, age-related macular degeneration (drusen
formulation, pigment abnormality, atrophy AMD, or exudative AMD in the early stage
of AMD), diabetic retinopathy (simple diabetic retinopathy, preproliferative diabetic
retinopathy, or proliferative diabetic retinopathy), diabetic macular edema, proliferative
vitreoretinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy,
retinal hemangioma proliferation, retinal vein occulusion, retinal artery occlusion,
cone dystrophy, retinal detachment, or pigmentary degeneration of the retina. Particularly,
the compound of the present invention can be suitably used for treatment or prevention
of atrophy AMD and a treatment or prevention of eye diseases accompanied by retinochoroidal
disorders.
[0114] According to the present invention, the therapeutic medicine or preventive medicine
for inflammatory diseases, diseases caused by lipid oxidation, or retinochoroidal
disorders (hereinafter, also simply referred to as "therapeutic /preventive medicine)
contains at least one selected from the phenylimidazole derivative represented any
of Formula (I) or (II), a pharmacologically acceptable salt thereof, and metabolites
thereof and preferably contains only one thereof as an active ingredient. The metabolites
of the phenylimidazole derivative or a salt thereof are substances obtained as a result
of a chemical reaction of the phenylimidazole derivative or a salt thereof in the
body.
[0115] In the therapeutic /preventive medicine of the present invention, the therapeutically
effective amount of the compound according to the present invention can be suitably
selected by considering the age, the weight, the symptoms of a patient, the physical
constitution of the patient, and the dosage form. The therapeutically effective daily
dose is normally in the range of 0.017 mg/day to 33.3 mg/day based on 1 kg of body
weight, is preferably in the range of 0.17 mg/day to 11.7 mg/day based on 1 kg of
body weight, and is more preferably in the range of 1.7 mg/day to 3.3 mg/day based
on 1 kg of body weight. For example, in a case where the compound of the present invention
is administered to a person whose body weight is 60 kg, the dose of the compound is
in the range of 1 mg/day to 2.0 g/day, is preferably in the range of 10 mg/day to
700 mg/day, and is more preferably in the range of 100 mg/day to 200 mg/day. However,
the dose of the compound can be set to be in a range other than the above-described
ranges by considering the symptoms of the patient, the physical constitution of the
patient, the dosage form, and the like.
[0116] The therapeutic /preventive medicine of the present invention can be administered
to a target using any method known to a person skilled in the art, such as an oral
administration, a parenteral administration, a nasal administration, an intravascular
administration, a cancer vicinity administration, a transmucosal administration, a
transdermal administration, an intramuscular administration, an intranasal administration,
an intravenous administration, an intradermal administration, a subcutaneous administration,
a sublingual administration, an intraperitoneal administration, an intraventricular
administration, an intracranial administration, an intravaginal administration, an
inhalation administration, an intrarectal administration, an intratumor administration
or a delivery by a ribosome. In addition, the compound can be locally administered
by applying the compound to mucosal cells, for example, applying the compound to skin
or an eye. Moreover, the compound can be administered to a target by an inhalation
or using a method of aerosol formulation.
[0117] The therapeutic/preventive medicine of the present invention is formulated as solid
or liquid formulation. Examples of the solid formulation include tablets, soft capsules,
hard capsules, pills, granules, pellets, powder, and sustained-release products. Examples
of the liquid formulation include solutions, suspensions, dispersants, emulsions,
oils, injections, and aerosols.
[0118] The solid formulation is suitable for oral administration or nasal administration.
The liquid formulation is suitable for oral administration, nasal administration,
intravenous administration, intraarterial administration, or intramuscular administration.
Formulations suitable for local administration to the body surface include a solution,
a suspension, an emulsion, a gelling agent, an ointment, creams, lotions, and drops
are exemplary examples. As suppository administration, rectal suppository or urethral
suppository is an exemplary example. The therapeutic/preventive medicine of the present
invention can be administered subcutaneous implantation of a sustained-release pellet.
The therapeutic/preventive medicine of the present invention can be delivered to tissues
by vesicles, specifically, liposomes.
[0119] The solid formulation may include a binding agent such as gum Arabic, corn starch,
gelatin, carbomer, ethyl cellulose, guar gum, hydroxy propyl cellulose, hydroxy propyl
methyl cellulose, povidone, or magnesium stearate; a lubricant such as stearic acid,
magnesium stearate, polyethylene glycol, sodium lauryl sulfate, starch, gum Arabic,
polyvinyl pyrrolidone, gelatin, or a cellulose ether derivative; an excipient such
as citrate, propyl gallate, gum, starch (for example, corn starch, pregeletanized
starch, or gelatinized starch), saccharide (for example, lactose, mannitol, sucrose,
or dextrose), gelatin, a cellulose-based material (for example, microcrystalline cellulose),
or polymethyl acrylate; a diluent such as lactose, sucrose, dicalcium phosphate, calcium
carbonate, magnesium oxide, or talc; a disintegrator such as corn starch, white potato
starch, alginic acid, silicon dioxide, sodium croscarmellose, crospovidone, guar gum,
or sodium starch glycolate; a colorant; a flavoring agent; a fluidizing inducer; a
melting agent; a buffering agent of pH and ion strength of Tris-HCl, acetate, or phosphate;
an additive such as albumin or gelatin that inhibit absorption in the surface; and
adjuvant.
[0120] The liquid formulation may include injectable organic ester such as propylene glycol,
polyethylene glycol, or ethyl oleate; water, an alcoholic/aqueous solution, cyclodextrin,
aqueous dextrose, an emulsion containing physiological saline and a buffering base,
or a suspension; peanul oil, soybean oil, mineral oil, olive oil, petroleum such as
sunflower seed oil or fish liver oil, animal oil, vegetable oil, and synthetic oil;
a sweetening agent such as thimerosal, benzyl alcohol, or paraben; a thickener such
as carbomer, colloidal silicon dioxide, ethyl cellulose, or guar gum; a melting agent,
a preservative, an emulsifier such as carbomer, hydroxy propyl cellulose, or sodium
lauryl sulfate; a suspending agent, a diluent, aspartame, and citric acid. In a case
of parenteral administration and intravenous administration, minerals or other substances
compatible with selected injection or a delivery system can be included.
[0121] Examples of components which may be contained include a cleanser such as Tween 20,
Tween 80, Pluronic F68, or a bile salt; a surfactant such as a protease inhibitor
or sodium lauryl sulfate; a permeation enhancer; a solubilizing agent such as cremophor,
glycerol, polyethylene glycerol, benzlkonium chloride, benzyl benzoate, cyclodextrin,
sorbitan ester, or stearic acid; an antioxidant such as ascorbic acid, sodium pyrosulfite,
or butylated hydroxy anisole; a stabilizer such as hydroxy propyl cellulose or hydroxy
propyl methyl cellulose; a fluidizing auxiliary such as colloidal silicon dioxide;
a plasticizer such as diethyl phthalate or triethyl citrate; a polymer coating agent
such as poloxamer or poloxamine; and a coating agent and a thin film forming agent
such as ethyl cellulose, acrylate, or polymethacrylate. In addition, parenteral vehicles
(for subcutaneous, intravenous, intraarterial, or intramuscular injection) may include
a sodium chloride solution, Ringer's dextrose, dextrose, sodium chloride, a lactated
Ringer's solution, and nonvolatile oil. Intravenous vehicles may include electrolyte
supplements using a body fluid, a nutrient supplement, and Ringer's dexterous as bases.
[0122] The therapeutic/preventive medicine of the present invention may be a release controlling
formulation, that is, a formulation in which the compound of the present invention
is released over a certain period of time after administration. The release controlling
formulation or a sustained release formulation contains a formulation in a lipophilic
depot formulation (such as fatty acids, a brazing filler metal, or oil).
[0123] The therapeutic/preventive medicine of the present invention may be a rapid release
formulation, that is, a formulation in which all compounds are released immediately
after administration.
[0124] The therapeutic/preventive medicine of the present invention can be delivered using
a release controlling system. For example, the therapeutic/preventive medicine can
be administered using intravenous injection, an implantable osmotic pump, a transdermal
patch, liposome, or other administration methods. The release controlling system can
be placed in the vicinity of a treatment target, that is, a retinochoroidal lesion.
[0126] The formulation for oral administration can be obtained by mixing the compound of
the present invention with a common additive such as a vehicle, a stabilizer, or an
inactive diluent according to the purpose thereof and converting the mixture into
a shape suitable for administration such as a tablet, a coated tablet, a hard or soft
gelatin capsule, or an aqueous, alcoholic, or oily solution according to a common
method.
[0127] The formulation for parenteral formulation can be obtained by converting the compound
of the present invention a solution, a suspension, or an emulsion, if necessary, together
with a common substance suitable for the purpose such as a solubilizing agent or the
like.
[0128] The amount of the compound according to the present invention in the therapeutic/preventive
medicine of the present invention is preferably in the range of 1% by weight to 99%
by weight, and more preferably in the range of 5% by weight to 75% by weight. The
amount can be determined according to the administration manner. The therapeutic/preventive
medicine may contain 1% by weight to 99% by weight of a pharmaceutical carrier or
excipient. The remainder of the therapeutic/preventive medicine is preferably made
into an appropriate pharmaceutical carrier or excipient.
[0129] The therapeutic/preventive medicine of the present invention can be administered
as medicine for the above-described diseases in an arbitrary manner.
[0130] The injections may contain an aqueous solution, a non-aqueous solution, a suspension,
or an emulsion which is sterile. Specific examples of an aqueous solution and a diluent
of a suspension include distilled water for an injection and physiological saline.
Specific examples of a non-aqueous solution and a diluent of a suspension include
vegetable oil such as propylene glycol, polyethylene glycol, or olive oil; alcohols
such as ethanol; and polysorbate (trade name). These compositions may further contain
additives such as a tonicity agent, a preservative, a wetting agent, an emulsifier,
a dispersant, a stabilizer (for example, lactose), a solubilizing agent, and a dissolution
assisting agent. These can be used by being filtered through a bacteria-retaining
filter, producing a solid composition of a sterilizing agent, and dissolving the composition
in sterile water or a sterile solution for injection before use.
[0131] In a case where the therapeutic/preventive medicine of the present invention is used
as a suppository, a carrier which is gradually dissolved in a body as a carrier, for
example, a carrier in which polyoxyethylene glycol or polyethylene glycol (hereinafter,
referred to as "PEG"), specifically, PEG1000 and/or PEG4000 is used and 0.5% by weight
to 50% by weight of the compound of the present invention is dispersed therein, is
an exemplary example.
[0132] In a case where the therapeutic/preventive medicine of the present invention is used
as a liquid formulation, a solution or a suspension obtained by dissolving or dispersing
0.5% by weight to 50% by weight of the compound according to the present invention
in a carrier, such as a water, a saline solution, a dextrose aqueous solution, glycerol,
ethanol or the like, optionally with a pharmaceutical adjuvant. At least one from
among other inhibitors for retinal oxidative disorders which are not reacted with
active ingredients may be added to the compound of the present invention or other
components having efficacy of medicine may be contained therein.
[0133] In a case where the compound of the present invention is used as an ophthalmic solution,
at least one compound of the present invention is added to a base solvent which is
normally used to obtain an aqueous solution or a suspension, and then the pH thereof
can be adjusted to be preferably in a range of 4 to 10 and to be more preferably in
a range of 5 to 9. It is preferable that an ophthalmic solution be subjected to a
sterilization treatment in order to obtain an aseptic product and the sterilization
treatment can be performed at any stage of the producing process.
[0134] The concentration of the compound of the present invention in the ophthalmic solution
is preferably 0.0001% to 10% (W/V), is more preferably in the range of 0.001% to 3%
(W/V), and is particularly preferably in the range of 0.01% to 1% (W/V). The dosage
thereof can be once a day or divided into several times a day and several drops at
each time, according to the symptoms of a patient or the body constitution of the
patient. The above-described dosage is only a guide and the amount of the ophthalmic
solution administered can be beyond the range.
[0135] Various additives such as a buffering agent, a tonicity agent, a preservative, a
pH adjusting agent, a thickener, a chelating agent, and a solubilizing agent may be
suitably added to the ophthalmic solution within the range not being reacted with
the compound of the present invention.
[0136] Specific examples of the buffering agent include a citrate buffering agent, a tartrate
buffering agent, an acetate buffering agent, and amino acid. Specific examples of
the tonicity agent include saccharides such as sorbitol, glucose, and mannitol; polyhydric
alcohols such as glycerin, polyethylene glycol, and propylene glycol; and salts such
as sodium chloride. Specific examples of the preservative include paraoxybenzoates
such as methyl paraoxybenzoate and ethyl paraoxybenzoate; aryl alkyl alcohols such
as benzyl alcohol and phenethyl alcohol; and sorbic acid or a salt thereof. Specific
examples of the pH adjusting agent include phosphoric acid and sodium hydroxide. Specific
examples of the thickener include hydroxy ethyl cellulose, hydroxy propyl cellulose,
methyl cellulose, hydroxy propyl methyl cellulose, carboxy methyl cellulose, and salts
of these. Specific examples of the chelating agent include sodium edetate, sodium
citrate, and fused sodium phosphate. Specific examples of the solubilizing agent include
ethanol and polyoxyethylene hardened castor oil.
[0137] In a case where the compound of the present invention is an eye ointment, at least
one compound from among the compounds of the present invention can be mixed with an
eye ointment which is normally used, for example, purified lanolin, white petrolatum,
macrogol, plastibase, or liquid paraffin and it is preferable that the mixture be
subjected to a sterilization treatment in order to obtain an aseptic product.
[0138] The concentration of the compound of the present invention in the eye ointment is
preferably 0.0001% to 10% (W/W), is more preferably in the range of 0.001% to 3% (W/W),
and is particularly preferably in the range of 0.01% to 1% (W/W). The dosage thereof
can be once a day or divided into several times a day according to the symptoms of
a patient or the body constitution of the patient and several drops can be respectively
administered. The above-described dosage is only a guide and the eye ointment can
be administered beyond that range.
Examples
[0139] The present invention will be described in detail with reference to Examples below.
However, the technical scope of the present invention is not limited to the following
Examples.
(Example 1)
Production of 4-acetyl-1-(4-amino-3-imidazole-1-yl-phenyl)piperazine (compound 1-1)
Process 1: production of 2-imidazole-1-yl-4-fluoronitrobenzene
[0140] 4.00 g of 2,4-difluoronitrobenzene, 1.71 g of imidazole, and 3.82 g of potassium
carbonate were suspended in 40 mL of N-N-dimethylformamide and the solution was stirred
at room temperature for one day. Water was added to the reaction solution, the solution
was extracted by chloroform three times, washed with saturated saline, dried by anhydrous
magnesium sulfate, and concentrated under reduced pressure. The residue was purified
with silica gel column chromatography (chloroform:ethyl acetate =1:1 (volume ratio)),
thereby obtaining 3.87 g of a target object.
Process 2: production of 2-imidazole-1-yl-4-(4-acetylpiperazine-1-yl) nitrobenzene
[0141] 3.87 g of 2-imidazole-1-yl-4-fluoronitrobenzene, 2.64 g of 1-acetylpiperazine, and
3.36 g of potassium carbonate were suspended in 9 mL of dimethyl sulfoxide, and the
solution was stirred at 100°C for 2 hours. Water was added to the reaction solution,
and deposited crystals were separated by filtration, followed by washing with water
and ether in order. Chloroform and methanol were added to the obtained solid, followed
by drying by anhydrous magnesium sulfate and concentrating under reduced pressure.
The residue was purified with silica gel column chromatography (chloroform:methanol
=9:1 (volume ratio)), thereby obtaining 5.78 g of a target object.
Process 3: production of 4-acetyl-1-(4-amino-3-imidazole-1-yl-phenyl)piperazine
[0142] 3 g of 2-imidazole-1-yl-4-(4-acetylpiperazine-1-yl)nitrobenzene and 0.2 g of 10%
Pd/C were added to 50 mL of ethanol and the solution was stirred at 50°C and at a
hydrogen pressure of 0.45 MPa for 1.5 hours. After the solution was cooled, the reaction
solution was filtered using celite, the solvent was distilled under reduced pressure,
and the residue was purified with silica gel column chromatography (Fuji Silysia Silica
Gel (NH): chloroform). The obtained crystals were recrystallized using ethyl acetate-methanol-hexane,
thereby obtaining 1.6 g of a target object having a melting point of 94°C to 97°C.
(Example 2)
Process 1: production of 3-acetylamino-1-(4-nitro-3-imidazole-1-yl-phenyl)pyrrolidine
[0143]
[0144] 2.07 g of 2-imidazole-1-yl-4-fluoronitrobenzene, 1.54 g of 3-acetylaminopyrrolidine,
and 1.66 g of potassium carbonate were suspended in 20 mL of N,N-dimethylformamide,
and the solution was stirred at 80°C for 2 hours. The reaction solution was dropwise
added to ice-water, and deposited crystals were separated by filtration and washed
with water, thereby obtaining 2.5 g of a target object.
Process 2: production of 3-acetylamino-1-(4-amino-3-imidazole-1-yl-phenyl)pyrrolidine
[0145]
[0146] 2 g of 3-acetylamino-1-(4-nitro 3-imidazole-1-yl-phenyl)pyrrolidine, 1.2 g of 20%
Pd(OH)
2/C, and 1.5 g of ammonium formate were added to 25 mL of ethanol and the solution
was refluxed for 30 minutes. After the solution was cooled, the reaction solution
was filtered using celite, the solvent was distilled under reduced pressure, and the
residue was purified with silica gel column chromatography (Fuji Silysia Silica Gel
(NH): chloroform). The obtained crystals were recrystallized using ethyl acetate-methanol-hexane,
thereby obtaining 1.02 g of a target object having a melting point of 169°C to 171°C.
[0147] Examples of the compound of the present invention including compounds described
in Examples above are listed in Tables 1 to 4. In addition, Table 1 shows a compound
represented by Formula (Ia), Table 2 shows a compound represented by Formula (Ib),
Table 3 shows a compound represented by Formula (IIa), and Table 4 shows a compound
represented by Formula (IIb). Me represents a methyl group, Et represents an ethyl
group,
nPr represents a n-propyl group,
iPr represents an isopropyl group,
cPr represents a cyclopropyl group,
nBu represents a n-butyl group,
iBu represents an isobutyl group, and Ac represents an acetyl group. A, B
1, B
2, R
1a, R
1c, (R
2)
a, (R
3)
b, (R
4)
c, (R
5)
d, (R
6)
n, and (R
6)
m represent a substituent in a compound represented by Formula (Ia), (Ib), (IIa), or
(IIb). Further, *1 represents a binding position of an imidazole-1-yl group.
[Table 1]
[0148]
Table 1
No. |
R1a |
*1 |
(R2)a |
(R3)b |
(R4)c |
(R5)d |
(R6)n |
1-1 |
Me |
3-position |
4-NH2 |
- |
- |
- |
- |
1-2 |
Me |
3-position |
4-NH2 |
- |
- |
2-Me |
- |
1-3 |
Me |
3-position |
4-NH2 |
- |
- |
4-Me |
- |
1-4 |
Me |
3-position |
4-NH2 |
- |
- |
2-CF3 |
- |
1-5 |
Me |
3-position |
4-NHAc |
- |
- |
- |
- |
1-6 |
Me |
3-position |
4-NHCOAc |
- |
- |
- |
- |
1-7 |
Me |
3-position |
4-NMe2 |
- |
- |
- |
- |
1-8 |
H |
3-position |
4-NH2 |
2-F |
- |
- |
- |
1-9 |
cPr |
3-position |
4-NH2 |
- |
- |
- |
- |
1-10 |
OtBu |
3-position |
4-NH2 |
- |
- |
- |
- |
1-11 |
CH2OMe |
3-position |
4-NH2 |
- |
- |
- |
- |
1-12 |
CH2CF3 |
3-position |
4-NH2 |
2-Me |
- |
- |
- |
1-13 |
CH=CH2 |
3-position |
4-NH2 |
- |
4-CN |
- |
- |
1-14 |
NMe2 |
3-position |
4-NH2 |
- |
- |
- |
- |
1-15 |
Morpholin-4-yl |
3-position |
4-NH2 |
- |
- |
- |
- |
1-16 |
Me |
3-position |
4-OMe |
- |
- |
- |
- |
1-17 |
Me |
3-position |
4-OH |
- |
- |
- |
- |
1-18 |
Me |
3-position |
4-OAc |
- |
- |
- |
- |
1-19 |
Et |
3-position |
4-CN |
- |
- |
- |
- |
1-20 |
Me |
3-position |
4-CH2NHiPr |
- |
4-CH2OH |
- |
- |
1-21 |
Me |
3-position |
4-NHSO2Me |
- |
|
2-Me |
- |
1-22 |
Me |
3-position |
4-N=CH(NMe2) |
- |
- |
4-Me |
- |
1-23 |
Me |
3-position |
4-NHCOCF3 |
- |
- |
5-Me |
- |
1-24 |
Me |
3-position |
4-NHCHO |
- |
- |
2,4-Me2 |
- |
1-25 |
Me |
3-position |
4-NHCOEt |
- |
- |
2-iPr |
- |
1-26 |
Me |
3-position |
4-NHCOcPr |
- |
- |
4-CF3 |
- |
1-27 |
Me |
3-position |
4-NHCOcPr |
- |
- |
2-Me |
- |
1-28 |
Me |
3-position |
4-NHCOCH2OMe |
- |
- |
- |
- |
1-29 |
Me |
3-position |
4-NHCOCH2NMe2 |
- |
- |
- |
- |
1-30 |
Me |
3-position |
4-NHEt |
- |
- |
- |
- |
1-31 |
Me |
3-position |
4-NHiBu |
- |
- |
- |
- |
1-32 |
Me |
3-position |
4-NHCH2cPr |
- |
- |
- |
- |
[Table 2]
[0149] Continuation of Table 1
No. |
R1a |
*1 |
(R2)a |
(R3)b |
(R4)c |
(R5)d |
(R6)n |
1-33 |
Me |
3-position |
4-NHCH2C=CH |
- |
- |
- |
- |
1-34 |
Me |
3-position |
4-NHCO2Me |
- |
- |
- |
- |
1-35 |
Me |
3-position |
2-NH2 |
- |
- |
2-Me |
- |
1-36 |
Me |
3-position |
2-NH2 |
- |
- |
3-Me |
- |
1-37 |
Me |
3-position |
4-NH2-5-NHiPr |
- |
- |
- |
- |
1-38 |
Me |
3-position |
4-NH2-5-NMe2 |
- |
- |
- |
- |
1-39 |
Me |
3-position |
4-NH2-5-OMe |
- |
- |
- |
- |
1-40 |
Me |
3-position |
4-NH2-5-OEt |
- |
- |
- |
- |
1-41 |
Me |
4-position |
3-NH2 |
- |
- |
- |
- |
1-42 |
Me |
4-position |
3-NHAc |
- |
- |
- |
- |
1-43 |
Me |
4-position |
3-NHCOAc |
- |
- |
- |
- |
1-44 |
Me |
4-position |
3-NMe2 |
- |
- |
- |
- |
1-45 |
H |
4-position |
3-NH2 |
- |
- |
- |
- |
1-46 |
cPr |
4-position |
3-NH2 |
- |
- |
- |
- |
1-47 |
OtBu |
4-position |
3-NH2 |
- |
- |
- |
- |
1-48 |
CH2OMe |
4-position |
3-NH2 |
- |
- |
- |
- |
1-49 |
CH2CF3 |
4-position |
3-NH2 |
- |
- |
- |
- |
1-50 |
NMe2 |
4-position |
3-NH2 |
- |
- |
- |
- |
1-51 |
Morpholin-4-yl |
4-position |
3-NH2 |
- |
- |
- |
- |
1-52 |
Me |
4-position |
3-OMe |
- |
- |
- |
- |
1-53 |
Me |
2-position |
4-NH2 |
- |
- |
- |
- |
1-54 |
Me |
2-position |
4-NHAc |
- |
- |
- |
- |
1-55 |
Me |
2-position |
4-NHCOAc |
- |
- |
- |
- |
1-56 |
Me |
2-position |
4-NMe2 |
- |
- |
- |
- |
1-57 |
H |
2-position |
4-NH2 |
- |
- |
- |
- |
1-58 |
cPr |
2-position |
4-NH2 |
- |
- |
- |
- |
1-59 |
OtBu |
2-position |
4-NH2 |
- |
- |
- |
- |
1-60 |
CH2OMe |
2-position |
4-NH2 |
- |
- |
- |
- |
1-61 |
CH2CF3 |
2-position |
4-NH2 |
- |
- |
- |
- |
1-62 |
NMe2 |
2-position |
4-NH2 |
- |
- |
- |
- |
1-63 |
Morpholin-4-yl |
2-position |
4-NH2 |
- |
- |
- |
- |
1-64 |
Me |
2-position |
4-OMe |
- |
- |
- |
- |
[Table 3]
[0150]
Table 2
No. |
A |
B1 |
*1 |
(R2)a |
(R3)b |
(R4)c |
(R5)d |
(R6)n |
2-1 |
N |
N-C(Me)=NOH |
3-position |
4-NH2 |
- |
- |
- |
- |
2-2 |
N |
N-C(Me)=NOH |
3-position |
4-NHAc |
- |
- |
- |
- |
2-3 |
N |
N-C(Me)=NOH |
3-position |
4-NHCOAc |
- |
- |
- |
- |
2-4 |
N |
N-C(Me)=NOH |
3-position |
4-NMe2 |
- |
- |
- |
- |
2-5 |
N |
N-SO2Me |
3-position |
4-NH2 |
- |
- |
- |
- |
2-6 |
N |
N-SO2Me |
3-position |
4-NH2 |
- |
- |
- |
- |
2-7 |
N |
N-SO2Me |
3-position |
4-NHAc |
- |
- |
- |
- |
2-8 |
N |
N-SO2Me |
3-position |
4-NHCOAc |
- |
- |
- |
- |
2-9 |
N |
N-SO2Me |
3-position |
4-NMe2 |
- |
- |
- |
- |
2-10 |
N |
N-SO2cPr |
3-position |
4-NH2 |
- |
- |
- |
- |
2-11 |
N |
N-SO2CH2OMe |
3-position |
4-NH2 |
- |
- |
- |
- |
2-12 |
N |
N-SO2CH2CF3 |
3-position |
4-NH2 |
- |
- |
- |
- |
2-13 |
N |
N-SO2NMe2 |
3-position |
4-NH2 |
- |
- |
- |
- |
2-14 |
CH |
N-CO2tBu |
3-position |
4-NH2 |
- |
- |
- |
- |
2-15 |
CH |
N-COMe |
3-position |
4-NH2 |
- |
- |
- |
- |
2-16 |
CH |
N-COMe |
3-position |
4-NHAc |
- |
- |
- |
- |
2-17 |
CH |
N-COMe |
3-position |
4-NHCOAc |
- |
- |
- |
- |
2-18 |
CH |
N-COMe |
3-position |
4-NMe2 |
- |
- |
- |
- |
2-19 |
CH |
N-COcPr |
3-position |
4-NH2 |
- |
- |
- |
- |
2-20 |
CH |
N-COCH2OMe |
3-position |
4-NH2 |
- |
- |
- |
- |
2-21 |
CH |
N-COCH2CF3 |
3-position |
4-NH2 |
- |
- |
- |
- |
2-22 |
CH |
N-CONMe2 |
3-position |
4-NH2 |
- |
- |
- |
- |
2-23 |
CH |
N-COMe |
3-position |
4-NHSO2Me |
- |
- |
- |
- |
2-24 |
CH |
N-COMe |
3-position |
4-N=CH(NMe2) |
- |
- |
- |
- |
2-25 |
CH |
N-COMe |
3-position |
4-NHCOCF3 |
- |
- |
- |
- |
[Table 4]
[0151]
Continuation of Table 2
No. |
A |
B1 |
*1 |
(R2)a |
(R3)b |
(R4)c |
(R5)d |
(R6)n |
2-26 |
CH |
N-COMe |
3-position |
4-NHCHO |
- |
- |
- |
- |
2-27 |
CH |
N-COMe |
3-position |
4-NHCOEt |
- |
- |
- |
- |
2-28 |
CH |
N-COMe |
3-position |
4-NHCOcPr |
- |
- |
- |
- |
2-29 |
CH |
N-COMe |
3-position |
4-NHCOcPr |
- |
- |
- |
- |
2-30 |
CH |
N-COMe |
3-position |
4-NHCOCH2OMe |
- |
- |
- |
- |
2-31 |
CH |
N-COMe |
3-position |
4-NHCOCH2NMe2 |
- |
- |
- |
- |
2-32 |
CH |
N-COMe |
3-position |
4-NHEt |
- |
- |
- |
- |
2-33 |
CH |
N-COMe |
3-position |
4-NHiBu |
- |
- |
- |
- |
2-34 |
CH |
N-COMe |
3-position |
4-NHCH2iPr |
- |
- |
- |
- |
2-35 |
CH |
N-COMe |
3-position |
4-NHCH2C≡CH |
- |
- |
- |
- |
2-36 |
CH |
N-COMe |
3-position |
4-NHCO2Me |
- |
- |
- |
- |
2-37 |
N |
C=O |
3-position |
4-NH2 |
- |
- |
- |
3-(CH2)3-5 |
2-38 |
N |
C=O |
3-position |
4-NH2 |
- |
- |
- |
3-(CH2)2-5 |
2-39 |
N |
C=O |
3-position |
4-NHAc |
- |
- |
- |
3-(CH2)3-5 |
2-40 |
N |
C=O |
3-position |
4-NHCOAc |
- |
- |
- |
3-(CH2)3-5 |
2-41 |
N |
C=O |
3-position |
4-NMe2 |
- |
- |
- |
3-(CH2)3-5 |
[Table 5]
[0152]
Table 3
No. |
R1a |
R1c |
*1 |
(R2)a |
(R3)b |
(R4)c |
(R5)d |
(R6)m |
3-1 |
Me |
H |
3-position |
4-NH2 |
- |
- |
- |
- |
3-2 |
Me |
H |
3-position |
4-NH2 |
- |
- |
2-Me |
- |
3-3 |
Me |
H |
3-position |
4-NH2 |
- |
- |
4-Me |
- |
3-4 |
Me |
H |
3-position |
4-NH2 |
- |
- |
2-CF3 |
- |
3-5 |
Me |
H |
3-position |
4-NHAc |
- |
- |
- |
- |
3-6 |
Me |
H |
3-position |
4-NHCOAc |
- |
- |
- |
- |
3-7 |
Me |
H |
3-position |
4-NMe2 |
- |
- |
- |
- |
3-8 |
H |
H |
3-position |
4-NH2 |
2-F |
- |
- |
- |
3-9 |
cPr |
H |
3-position |
4-NH2 |
- |
- |
- |
- |
3-10 |
OtBu |
H |
3-position |
4-NH2 |
- |
- |
- |
- |
3-11 |
CH2OMe |
H |
3-position |
4-NH2 |
- |
- |
- |
- |
3-12 |
CH2CF3 |
H |
3-position |
4-NH2 |
2-Me |
- |
- |
- |
3-13 |
CH=CH2 |
H |
3-position |
4-NH2 |
- |
4-CN |
- |
- |
3-14 |
NMe2 |
H |
3-position |
4-NH2 |
- |
- |
- |
- |
3-15 |
Morpholin-4-yl |
H |
3-position |
4-NH2 |
- |
- |
- |
- |
3-16 |
Me |
H |
3-position |
4-OMe |
- |
- |
- |
- |
3-17 |
Me |
H |
3-position |
4-OH |
- |
- |
- |
- |
3-18 |
Me |
H |
3-position |
4-OAc |
- |
- |
- |
- |
3-19 |
Et |
H |
3-position |
4-CN |
- |
- |
- |
- |
3-20 |
Me |
H |
3-position |
4-CH2NHiPr |
- |
4-CH2OH |
- |
- |
3-21 |
Me |
H |
3-position |
4-NHSO2Me |
- |
- |
2-Me |
- |
3-22 |
Me |
H |
3-position |
4-N=CH(NMe2) |
- |
- |
4-Me |
- |
3-23 |
Me |
H |
3-position |
4-NHCOCF3 |
- |
- |
5-Me |
- |
3-24 |
Me |
H |
3-position |
4-NHCHO |
- |
- |
2,4-Me2 |
- |
3-25 |
Me |
H |
3-position |
4-NHCOEt |
- |
- |
2-iPr |
- |
3-26 |
Me |
H |
3-position |
4-NHCOcPr |
- |
- |
4-CF3 |
- |
3-27 |
Me |
H |
3-position |
4-NHCOiPr |
- |
- |
2-Me |
- |
3-28 |
Me |
H |
3-position |
4-NHCOCH2OMe |
- |
- |
- |
- |
3-29 |
Me |
H |
3-position |
4-NHCOCH2NMe2 |
- |
- |
- |
- |
3-30 |
Me |
H |
3-position |
4-NHEt |
- |
- |
- |
- |
3-31 |
Me |
H |
3-position |
4-NHiBu |
- |
- |
- |
- |
3-32 |
Me |
H |
3-position |
4-NHCH2cPr |
- |
- |
- |
- |
[Table 6]
[0153]
Continuation of Table 3
No. |
R1a |
R1c |
*1 |
(R2)a |
(R3)b |
(R4)c |
(R5)d |
(R6)m |
3-33 |
Me |
H |
3-position |
4-NHCH2C≡CH |
- |
- |
- |
- |
3-34 |
Me |
H |
3-position |
4-NHCO2Me |
- |
- |
- |
- |
3-35 |
Me |
H |
3-position |
2-NH2 |
- |
- |
2-Me |
- |
3-36 |
Me |
H |
3-position |
2-NH2 |
- |
- |
3-Me |
- |
3-37 |
Me |
H |
3-position |
4-NH2-5-NHiPr |
- |
- |
- |
- |
3-38 |
Me |
H |
3-position |
4-NH2-5-NMe2 |
- |
- |
- |
- |
3-39 |
Me |
H |
3-position |
4-NH2-5-OMe |
- |
- |
- |
- |
3-40 |
Me |
H |
3-position |
4-NH2-5-OEt |
- |
- |
- |
- |
3-41 |
Me |
H |
4-position |
3-NH2 |
- |
- |
- |
- |
3-42 |
Me |
H |
4-position |
3-NHAc |
- |
- |
- |
- |
3-43 |
Me |
H |
4-position |
3-NHCOAc |
- |
- |
- |
- |
3-44 |
Me |
H |
4-position |
3-NMe2 |
- |
- |
- |
- |
3-45 |
H |
H |
4-position |
3-NH2 |
- |
- |
- |
- |
3-46 |
cPr |
H |
4-position |
3-NH2 |
- |
- |
- |
- |
3-47 |
OtBu |
H |
4-position |
3-NH2 |
- |
- |
- |
- |
3-48 |
CH2OMe |
H |
4-position |
3-NH2 |
- |
- |
- |
- |
3-49 |
CH2CF3 |
H |
4-position |
3-NH2 |
- |
- |
- |
- |
3-50 |
NMe2 |
H |
4-position |
3-NH2 |
- |
- |
- |
- |
3-51 |
Morpholin-4-yl |
H |
4-position |
3-NH2 |
- |
- |
- |
- |
3-52 |
Me |
H |
4-position |
3-OMe |
- |
- |
- |
- |
3-53 |
Me |
H |
2-position |
4-NH2 |
- |
- |
- |
- |
3-54 |
Me |
H |
2-position |
4-NHAc |
- |
- |
- |
- |
3-55 |
Me |
H |
2-position |
4-NHCOAc |
- |
- |
- |
- |
3-56 |
Me |
H |
2-position |
4-NMe2 |
- |
- |
- |
- |
3-57 |
H |
H |
2-position |
4-NH2 |
- |
- |
- |
- |
3-58 |
cPr |
H |
2-position |
4-NH2 |
- |
- |
- |
- |
3-59 |
OtBu |
H |
2-position |
4-NH2 |
- |
- |
- |
- |
3-60 |
CH2OMe |
H |
2-position |
4-NH2 |
- |
- |
- |
- |
3-61 |
CH2CF3 |
H |
2-position |
4-NH2 |
- |
- |
- |
- |
3-62 |
NMe2 |
H |
2-position |
4-NH2 |
- |
- |
- |
- |
3-63 |
Morpholin-4-yl |
H |
2-position |
4-NH2 |
- |
- |
- |
- |
3-64 |
Me |
H |
2-position |
4-OMe |
- |
- |
- |
- |
[Table 7]
[0154]
Table 4
No. |
A |
B2 |
*1 |
(R2)a |
(R3)b |
(R4)c |
(R5)d |
(R6)m |
4-1 |
N |
NH-C(Me)=NOH |
3-position |
4-NH2 |
- |
- |
- |
- |
4-2 |
N |
NH-C(Me)=NOH |
3-position |
4-NHAc |
- |
- |
- |
- |
4-3 |
N |
NH-C(Me)=NOH |
3-position |
4-NHCOAc |
- |
- |
- |
- |
4-4 |
N |
NH-C(Me)=NOH |
3-position |
4-NMe2 |
- |
- |
- |
- |
4-5 |
N |
NH-SO2Me |
3-position |
4-NH2 |
- |
- |
- |
- |
4-6 |
N |
NH-SO2Me |
3-position |
4-NH2 |
- |
- |
- |
- |
4-7 |
N |
NH-SO2Me |
3-position |
4-NHAc |
- |
- |
- |
- |
4-8 |
N |
NH-SO2Me |
3-position |
4-NHCOAc |
- |
- |
- |
- |
4-9 |
N |
NH-SO2Me |
3-position |
4-NMe2 |
- |
- |
- |
- |
4-10 |
N |
N-SO2cPr |
3-position |
4-NH2 |
- |
- |
- |
- |
4-11 |
N |
NH-SO2CH2OMe |
3-position |
4-NH2 |
- |
- |
- |
- |
4-12 |
N |
NH-SO2CH2CF3 |
3-position |
4-NH2 |
- |
- |
- |
- |
4-13 |
N |
NH-SO2NMe2 |
3-position |
4-NH2 |
- |
- |
- |
- |
4-14 |
CH |
NH-CO2tBu |
3-position |
4-NH2 |
- |
- |
- |
- |
4-15 |
CH |
NH-COMe |
3-position |
4-NH2 |
- |
- |
- |
- |
4-16 |
CH |
NH-COMe |
3-position |
4-NHAc |
- |
- |
- |
- |
4-17 |
CH |
NH-COMe |
3-position |
4-NHCOAc |
- |
- |
- |
- |
4-18 |
CH |
NH-COMe |
3-position |
4-NMe2 |
- |
- |
- |
- |
4-19 |
CH |
NH-COcPr |
3-position |
4-NH2 |
- |
- |
- |
- |
4-20 |
CH |
NH-COCH2OMe |
3-position |
4-NH2 |
- |
- |
- |
- |
4-21 |
CH |
NH-COCH2CF3 |
3-position |
4-NH2 |
- |
- |
- |
- |
4-22 |
CH |
NH-CONMe2 |
3-position |
4-NH2 |
- |
- |
- |
- |
4-23 |
CH |
NH-COMe |
3-position |
4-NHSO2Me |
- |
- |
- |
- |
4-24 |
CH |
NH-COMe |
3-position |
4-N=CH(NMe2) |
- |
- |
- |
- |
4-25 |
CH |
NH-COMe |
3-position |
4-NHCOCF3 |
- |
- |
- |
- |
[Table 8]
[0155]
Continuation of Table 4
No. |
A |
B2 |
*1 |
(R2)a |
(R3)b |
(R4)c |
(R5)d |
(R6)m |
4-26 |
CH |
NH-COMe |
3-position |
4-NHCHO |
- |
- |
- |
- |
4-27 |
CH |
NH-COMe |
3-position |
4-NHCOEt |
- |
- |
- |
- |
4-28 |
CH |
NH-COMe |
3-position |
4-NHCOcPr |
- |
- |
- |
- |
4-29 |
CH |
NH-COMe |
3-position |
4-NHCOiPr |
- |
- |
- |
- |
4-30 |
CH |
NH-COMe |
3-position |
4-NHCOCH2OMe |
- |
- |
- |
- |
4-31 |
CH |
NH-COMe |
3-position |
4-NHCOCH2NMe2 |
- |
- |
- |
- |
4-32 |
CH |
NH-COMe |
3-position |
4-NHEt |
- |
- |
- |
- |
4-33 |
CH |
NH-COMe |
3-position |
4-NHiBu |
- |
- |
- |
- |
4-34 |
CH |
NH-COMe |
3-position |
4-NHCH2cPr |
- |
- |
- |
- |
4-35 |
CH |
NH-COMe |
3-position |
4-NHCH2C≡CH |
- |
- |
- |
- |
4-36 |
CH |
NH-COMe |
3-position |
4-NHCO2Me |
- |
- |
- |
- |
[0156] Physical properties of some compounds listed in Tables 1 to 4 will be shown below.
mp indicates a melting point and vis. indicates that the compound is a viscous oil-like
compound.
1-1: mp 94°C to 97°C
1-2: mp 78°C to 83°C
1-5: mp 183°C to 185°C
1-6: mp 147°C to 149°C
1-7: mp 152°C to 154°C
1-8: mp 183°C to 184°C
1-9: vis.
1-10: vis.
1-11: vis.
1-12: mp 217°C to 219°C
1-14: mp 149°C to 150°C
1-15: vis.
1-16: vis.
2-4: mp 185°C to 188°C
2-5: mp 178°C to 179°C
2-14: vis.
2-37: vis.
3-1: mp 169°C to 171°C
(Preparation of formulation)
[0157] A formulation containing the compound of the present invention was prepared by the
following method.
[0158] Formulation Example 1: Preparation of an oral agent (active ingredient 10 mg tablets)
[0159] Compound of the present invention: 10.0 mg
Lactose: 81.4 mg
Cone starch: 20.0 mg
Hydroxy propyl cellulose: 4.0 mg
Carboxy methyl cellulose calcium: 4.0 mg
Magnesium stearate: 0.6 mg
Total: 120.0 mg
[0160] 50 g of the compound of the present invention, 407 g of lactose, and 100 g of cone
starch were uniformly mixed with each other using a fluidized granulation coating
device (manufactured by OKAWARAMFG CO., LTD.) so as to obtain the composition described
above. 200 g of a 10% hydroxy propyl cellulose aqueous solution was sprayed to the
mixture and granulated. After the mixture was dried, the mixture passed through a
20 mesh sieve, 20 g of carboxy methyl cellulose calcium and 3 g of magnesium stearate
were added thereto, and then tablets, each of which has a weight of 120 mg, were obtained
using a stamp mill having a dimension of 7 mm x 8.4 R with a rotary tableting machine
(manufactured by HATA TEKKOSHO CO., LTD.).
(Retinal light disorder model test)
[0161] The usefulness (improvement rate with respect to retinal light disorders) of the
compound of the invention was evaluated using a mouse model of retinal light disorders,
generally used as a model of retinal light disorders, (
Investigative Ophthalmology & Visual Science, 2002; vol. 43; pp. 1162 to 1167). Here, the improvement rate with respect to the retinal light disorders was calculated
based on the thickness of an outer nuclear layer (hereinafter, referred to as "ONL"),
which is strongly interfered especially by light application among a retinal cell
layers , in a tissue specimen of a perpendicular surface of an eyeball.
[0162] Moreover, in the present test, the ONL of a light application group to which only
a base was administered was degraded to 30% to 50% of a normal light group.
1. Preparation of test compound administration liquid
[0163] A test compound was dissolved or suspended in a solvent (1% (w/v) methyl cellulose
aqueous solution) and then an administration liquid was prepared so that the test
compound to be 30 mg/kg body weight. The dose was set to 10 mL/kg body weight.
2. Test and measurement method
[0164]
- 1) Test compound group:
A 5-week-old BALB/cCr-based male mouse (weight of approximately 20 g) was bred in
a dark place for 48 hours. Subsequently, the test compound administration liquid was
orally administered (30 mg/kg). After 30 minutes, 6000 lux to 5000 lux of white light
was continuously applied to the mouse for 2 hours. Next, the mouse was bred in a breeding
room with 50 lux of light for 4 days.
An anesthetic (secobarbital sodium) was intraperitoneally administered to anesthetize
the mouse and then the mouse was exsanguinated to die. The top portion of the right
eyeball was marked with a thread and the eyeball was extracted. The extracted eyeball
was immersed in a fixing solution I (4% formaldehyde + 0.25% glutaraldehyde) for approximately
3 hours. Next, the cornea was removed and then further immersed in the fixing solution
for 24 hours. Subsequently, the eyeball was immersed in a fixing solution II (10%
neutral buffered formalin) and then fixed. The eyeball was cut along with a longitudinal
section including the optic nerve papilla and subjected to hematoxylin and eosin staining,
thereby obtaining a tissue specimen.
- 2) Light application group:
The operation was performed in the same manner as the test compound group, except
that only the solvent was orally administered instead of the test compound administration
liquid.
- 3) Normal light group:
The operation was performed in the same manner as the test compound group, except
that only the solvent was orally administered instead of the test compound administration
liquid and the mouse was not continuously irradiated with 6000 lux to 5000 lux of
white light for 2 hours.
3. Evaluation method of tissue specimen
[0165] A retina 14 is formed of ten layers of a retinal pigment epithelial layer 1, a visual
cell layer 2, an external limiting membrane 3, an ONL 4, an outer plexiform layer
5, an inner nuclear layer 6, an inner plexiform layer 7, a ganglion cell layer 8,
an optic nerve fiber layer 9, and an internal limiting membrane 10, from outside to
inside (see Figs. 1 to 3). Degeneration is started due to light application from visual
cells, outer segments and inner segments of the visual cells are lost, and the ONL
is reduced (
Opthalmology clinic practice; 2002; vol. 5; pp. 93).
[0166] The ONL thickness in the tissue specimen was measured for every 200 µm between the
optic nerve papilla to where upwardly spaced by 1 mm from the optic nerve papilla
using Lumina Vision. The area (AUC) from the optic nerve papilla to where upwardly
spaced by 1 mm from the optic papilla in the graph was calculated as an ONL area.
4. Calculation formula of ONL thickness improvement rate (%)
[0167] ONL thickness improvement rate (%) = (1 - (AUC of normal light group - AUC of test
compound group)/(AUC of normal light group - AUC of light application group) x 100
5. Statistical processing
[0168] FT test between the normal light group and the light application group (one-side
test) and between the light application group and the test compound group (two-side
test) was performed according to the ONL area.
6. Test results
[0169] As a part of the test results, the ONL thickness improvement rates of the case where
the compounds of the present invention 1-1, 1-2, 1-8, 1-9, 1-10, 1-11, 1-12, 1-14,
1-15, 2-5, 2-14, 2-37, and 3-1 were used are shown in Table 5.
[0170] In addition, when 2-imidazole-1-yl-4-(acetylpiperazine-1-yl)nitrobenzene described
in PTL 2 was used as a reference example, the ONL thickness improvement rate was 29.2%.
[Table 9]
[0171]
Table 5
No. |
ONL thickness improvement rate (%) |
1-1 |
100.6 |
1-2 |
64.8 |
1-8 |
106.3 |
1-9 |
83.1 |
1-10 |
31.5 |
1-11 |
104 |
1-12 |
52.3 |
1-14 |
42.2 |
1-15 |
45.7 |
2-5 |
93.1 |
2-14 |
55.6 |
2-37 |
94.1 |
3-1 |
87.2 |
[0172] As seen from the results of the FT examination, the compound of the present invention
significantly suppressed a decrease of ONL thickness in the animal models of the retinal
light disorders when administered orally at 30 mg/kg. In other words, the compound
of the present invention exhibited treatment and/or prevention effects for retinal
light disorders in the models of the retinal light disorders.
(Cytochrome P450 inhibitory action)
[0173] An inhibitory action of the compound of the present invention with respect to CYP2D6
(dextromethorphan was used as a substrate) and CYP3A4 (midazolam and testosterone
were used as substrates) which are isozymes of cytochrome P450 (hereinafter, referred
to as "CYP") serving as a major drug-metabolizing enzyme was examined using human
liver microsomes.
[0174] Using human liver microsomes pooled as an enzyme source, 1.3 mM NADP as a coenzyme,
3.3 mM D-glucose-6-phosphate, and 0.4 U/mL D-glucose-6-phosphate dehydrogenase, the
corresponding substrate (5 µM dextromethorphan for CYP2D6, 5 µM midazolam or 50 µM
testosterone for CYP3A4) and the compound of the present invention were added such
that the final concentration became 0.1, 1, 10 µM and then incubated at 37°C for 10
minutes. The inhibition rate (%) of the compound of the present invention in each
concentration was calculated by quantifying metabolites (CYP2D6; dextrorphan, CYP3A4;
1-hydroxymidazolam or 6β hydroxytestosterone) using HPLC-MS/MS and setting the value
of the activity of an enzyme when drug was not incorporated therein as 100%. 50% inhibitory
concentration IC50 (µM) was calculated by drawing a straight line between the concentration
where the inhibition rate exceeds 50% and the concentration where the inhibition rate
is less than 50 % in a graph showing a relationship between the inhibition rate and
the concentration and interpolating the concentration that becomes 50% inhibition.
[0175] As a part of the test results, the inhibitory activity in the respective enzymes
of the compound 1-1 of the present invention is shown in Table 6. In addition, the
values in parentheses show the inhibition rates (%) in the shown concentration.
[Table 10]
[0176]
Table 6
|
IC50(µM) |
Isozyme |
CYP2D6 |
CYP3A4 |
Substrate |
Dextromethorphan |
Midazolam |
Testosterone |
1-1 |
>10 (36%) |
>10 (28%) |
>10 (6%) |
[0177] The compound of the present invention did not show an inhibitory action of exceeding
50% in 10 µM with respect to CYP2D6 and CYP3A4 serving as a major human drug-metabolizing
enzyme. This indicates that a drug interaction caused by taking the compound of the
present invention and another agent is small and this becomes a clinical advantage.
[0178] As described above, the compound of the present invention is useful as an active
ingredient of therapeutic medicine or preventive medicine for retinochoroidal disorders,
particularly, therapeutic medicine or preventive medicine for retinochoroidal diseases
accompanied by retinal light disorders. The therapeutic medicine or preventive medicine
of the present invention maintains excellent tissue migration properties through oral
administration and therapeutic effects or preventive effects can be expected with
respect to the retinal light disorders.
(15-lipoxygenase activity inhibitory action)
[0179] The inhibitory action of the compound of the present invention with respect to the
activity of the present enzyme was examined using rabbit reticulocyte-derived 15-lipoxygenase.
[0180] Rabbit reticulocyte-derived 15-lipoxygenase was reacted with 260 µM of linoleic acid
and the amount of 13-hydroperoxide which was a reaction product was measured using
an absorption spectrometer. 3 µM of the compound of the present invention dissolved
in dimethyl sulfoxide was added to the reaction system and the inhibition rate of
13-hydroperoxide generation (15-lipoxygenase activity inhibition rate) was measured.
[0181] From among several measurement results, the 15-lipoxygenase activity inhibition rate
of the compound 1-1 at a concentration of 3 µM according to the present invention
was 49%. That is, the 50% inhibitory concentration with respect to 15-lipoxygenase
activity was approximately 3 µM.
[0182] Since 15-lipoxygenase is an enzyme that oxidizes the lipid, oxidation of a cell membrane
is suppressed and the cell membrane is protected (
Journal of Neuroscience Research, 2008; vol. 86; pp. 904 to 909). In addition, since 15-lipoxygenase is an enzyme related to generation of prostaglandin
which is a mediator of an inflammatory reaction (
Progress in Lipid Research, 2006; vol. 45; pp. 334 to 356), the progress of the inflammatory reaction can be reduced by inhibiting the present
enzyme activity. As described above, it can be expected that cells are protected and
the progress of inflammation is reduced through a 15-lipoxygenase activity inhibitory
action by administering the compound of the present invention to a patient having
an inflammatory disease.
(Leukotriene A4 hydrolase activity inhibitory action)
[0183] The inhibitory action of the compound according to the present invention with respect
to the activity of the present enzyme was examined using guinea pig lung-derived leukotriene
A
4 hydrolase.
[0184] Dunkin-Hartley guinea pig lung-derived leukotriene A
4 hydrolase was reacted with 1.70 µg/mL of leukotriene A
4 and the amount of leukotriene B
4 which was a reaction product was measured by an enzyme-linked immunosorbent assay.
3 µM of the compound of the present invention dissolved in dimethyl sulfoxide was
added to the reaction system and the inhibition rate of leukotriene B
4 generation (leukotriene A
4 hydrolase activity inhibition rate) was measured.
[0185] From among several measurement results, the leukotriene A
4 hydrolase activity inhibition rate of the compound 1-1 according to the present invention
at a concentration of 3 µM was 14%.
[0186] The leukotriene A
4 hydrolase is an enzyme that generates leukotriene B
4, and the leukotriene B
4 is a strong chemical inducer that activates neutrophils and monocytes and has an
action of accumulating these cells. Thus, the activation of inflammatory cells is
suppressed and the progress of inflammation can be suppressed (
Agents Actions, 1986; vol. 17; pp. 366 to 367) by inhibiting the present enzyme activity. As described above, it can be expected
that the progress of inflammation is suppressed through a leukotriene A
4 hydrolase activity inhibitory action by administering the compound of the present
invention to a patient with an inflammatory disease.
(Leukotriene C4 synthase activity inhibitory action)
[0187] The inhibitory action according to the compound of the present invention with respect
to the activity of the present enzyme was examined using guinea pig lung-derived leukotriene
C
4 synthase.
[0188] Dunkin-Hartley guinea pig lung-derived leukotriene C
4 synthase was reacted with 2.50 µg/mL of leukotriene A
4 and the amount of leukotriene C
4 which was a reaction product was measured by an enzyme-linked immunosorbent assay.
3 µM of the compound of the present invention dissolved in dimethyl sulfoxide was
added to the reaction system and the inhibition rate of leukotriene C
4 generation (leukotriene C
4 synthase activity inhibition rate) was measured.
[0189] From among several measurement results, the leukotriene C
4 synthase activity inhibition rate of the compound 1-1 according to the present invention
at a concentration of 3 µM was 27%.
[0190] The leukotriene C
4 synthase is an enzyme that generates leukotriene C
4, and the leukotriene C
4 causes a contraction of the vascular smooth muscle. In addition, the leukotriene
C
4 promotes a secretion of mucus to an airway or a visceral tissue, and aggregates white
blood cells to an inflamed region by improving the vascular permeability of microvessels.
Therefore, vascular contraction and the progress of inflammation can be suppressed
by inhibiting the present enzyme activity (
Biochemical Pharmacology, 1985; vol. 34; pp. 2695 to 2704). As described above, it can be expected that the progress of inflammation is suppressed
through a leukotriene C
4 synthase activity inhibitory action by administering the compound of the present
invention to a patient with an inflammatory disease and nutrient supplies to tissues
and cells are secured by suppressing the vascular contraction.
(Thromboxane synthase activity inhibitory action)
[0191] The inhibitory action of the compound according to the present invention with respect
to the activity of the present enzyme was examined using human platelet-derived thromboxane
synthase.
[0192] Thromboxane synthase of human recombinant cells was reacted with 2.10 µM of prostaglandin
H
2 and the amount of thromboxane B
2 which was a reaction product was measured by an enzyme-linked immunosorbent assay.
3 µM of the compound according to the present invention dissolved in dimethyl sulfoxide
was added to the reaction system and the inhibition rate of thromboxane B
2 generation (thromboxane synthase activity inhibition rate) was measured.
[0193] From among several measurement results, the thromboxane synthase activity inhibition
rate of the compound 1-1 according to the present invention at a concentration of
3 µM was 32%.
[0194] The thromboxane synthase is an enzyme that generates thromboxane A
2, and the thromboxane A
2 causes a contraction of the vascular smooth muscle. In addition, the thromboxane
A
2 improves secretion of mucus to an airway or a visceral tissue, and aggregates white
blood cells to an inflamed region by improving the vascular permeability of microvessels.
Therefore, vascular contraction and the progress of inflammation can be suppressed
by inhibiting the present enzyme activity. As described above, it can be expected
that the progress of inflammation is suppressed through a thromboxane synthase activity
inhibitory action by administering the compound of the present invention to a patient
with an inflammatory disease. and nutrient supply to cells is secured by suppressing
the vascular contraction.
(Phospholipase A2-II activity inhibitory action)
[0195] The inhibitory action of the compound according to the present invention with respect
to the activity of the present enzyme was examined using rattlesnake-derived phospholipase
A
2-II.
[0196] The rattlesnake-derived phospholipase A
2-II was reacted with 0.030 µCi of 1-palmitoyl-2-[1-
14C]oleoyl-L-3-phosphatidylcholine and the amount of
14C oleate which was a reaction product was measured by a radiation measurement method.
3 µM of the compound according to the present invention dissolved in dimethyl sulfoxide
was added to the reaction system and the inhibition rate of
14C oleate generation (phospholipase A
2-II activity inhibition rate) was measured.
[0197] From among several measurement results, the phospholipase A
2-II activity inhibition rate of the compound 1-1 according to the present invention
at a concentration of 3 µM was 12%.
[0198] Since the phospholipase A
2-II is an enzyme related to generation of prostaglandin which is a mediator of an
inflammatory reaction, the progress of the inflammation reaction can be suppressed
by inhibiting the present enzyme activity. As described above, it can be expected
that cells are protected and the progress of inflammation is suppressed through a
phospholipase A
2-II activity inhibitory action by administering the compound of the present invention
to a patient with an inflammatory disease.
(Lipid peroxidase activity inhibitory action)
[0199] The inhibitory action of the compound according to the present invention with respect
to the activity of the present enzyme was examined using guinea pig liver microsome-derived
lipid peroxidase.
[0200] Dunkin-Hartley guinea pig lung-derived lipid peroxidase was reacted with 0.25 M of
polyvalent unsaturated fatty acids and the amount of malondialdehyde which was a reaction
product was measured by an absorbance determination method. 3 µM of the compound according
to the present invention dissolved in dimethyl sulfoxide was added to the reaction
system and the inhibition rate of malondialdehyde generation (lipid peroxidase activity
inhibition rate) was measured.
[0201] From among several measurement results, the lipid peroxidase activity inhibition
rate of the compound 1-1 according to the present invention at a concentration of
3 µM was 13%.
[0202] Since the lipid peroxidase excessively oxidizes lipids, the progress of oxidation
of cell membranes can be suppressed by inhibiting the present enzyme activity. As
described above, it can be expected that cells are protected through a lipid peroxidase
activity inhibitory action by administering the compound of the present invention
to a patient with a disease caused by lipid oxidation.
(MAP kinase 1 activity inhibitory action)
[0203] The inhibitory action of the compound of the present invention with respect to the
activity of the present enzyme was examined using human recombinant MAP kinase 1.
[0204] The human recombinant MAP kinase 1 was reacted with 50.0 µg/mL of myelin basic protein
and the amount of
32P phosphorylated myelin basic protein which was a reaction product was measured by
a radioactivity measurement method. 3 µM of the compound according to the present
invention dissolved in dimethyl sulfoxide was added to the reaction system and the
inhibition rate of
32P phosphorylated myelin basic protein generation (MAP kinase 1 activity inhibition
rate) was measured.
[0205] From among several measurement results, the MAP kinase 1 activity inhibition rate
of the compound 1-1 according to the present invention at a concentration of 3 µM
was 13%.
[0206] The MAP kinase 1 induces proliferation or differentiation of cells. Thus, when the
compound of the present invention is administered to a patient with an inflammatory
disease, it can be expected that the progress of inflammation is suppressed by inhibiting
differentiation or proliferation to inflammatory lymphocytes in an inflamed region
through the MAP kinase 1 activity inhibitory action.
[0207] As described above, since the compound of the present invention inhibits of the activities
of various enzymes worsening the inflammatory reaction, the compound is useful as
an active ingredient of therapeutic medicine or preventive medicine for various inflammatory
diseases. Further, since the compound of the present invention inhibits of the activity
of a lipid oxidation enzyme, the compound is useful as an active ingredient of therapeutic
medicine or preventive medicine for various diseases caused by lipid oxidation. The
therapeutic medicine or preventive medicine of the present invention maintains excellent
tissue migration properties through oral administration and therapeutic effects or
preventive effects can be expected with respect to inflammatory diseases and various
diseases caused by lipid oxidation.
Reference Signs List
[0208]
- 1:
- retinal pigment epithelial layer
- 2:
- visual cell layer
- 3:
- external limiting membrane
- 4:
- ONL
- 5:
- outer plexiform layer
- 6:
- inner nuclear layer
- 7:
- inner plexiform layer
- 8:
- ganglion cell layer
- 9:
- optic nerve fiber layer
- 10:
- internal limiting membrane
- 11:
- optic part of retina
- 12:
- ciliary part of retina
- 13:
- iridial part of retina
- 14:
- retina
- 15:
- choroid
- 16:
- sclera
- 17:
- optic nerve papilla
- 18:
- macular region
- 19:
- central fovea